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Liver diseases pose significant challenges to global public health. In the realm of drug discovery and development, overcoming 'on-target off-tissue' effects remains a substantial barrier for various diseases. In this study, we have pioneered a Liver-Targeting Chimera (LIVTAC) approach using a proteolysis-targeting chimera (PROTAC) molecule coupled to the liver-specific asialoglycoprotein receptor (ASGPR) through an innovative linker attachment strategy for the precise induction of target protein degradation within the liver. As a proof-of-concept study, we designed XZ1606, a mammalian bromodomain and extra-terminal domain (BET)-targeting LIVTAC agent, which not only demonstrated enduring tumor suppression (over 2 months) in combination with sorafenib but also an improved safety profile, notably ameliorating the incidence of thrombocytopenia, a common and severe on-target dose-limiting toxic effect associated with conventional BET inhibitors. These encouraging results highlight the potential of LIVTAC as a versatile platform for addressing a broad spectrum of liver diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Proteolysis targeting chimera (PROTAC) technology represents a groundbreaking development in drug discovery, leveraging the ubiquitin‒proteasome system to specifically degrade proteins responsible for the disease. PROTAC is characterized by its unique heterobifunctional structure, which comprises two functional domains connected by a linker. The linker plays a pivotal role in determining PROTAC's biodegradative efficacy. Advanced and rationally designed functional linkers for PROTAC are under development. Nonetheless, the correlation between linker characteristics and PROTAC efficacy remains under-investigated. Consequently, this study will present a multidisciplinary analysis of PROTAC linkers and their impact on efficacy, thereby guiding the rational design of linkers. We will primarily discuss the structural types and characteristics of PROTAC linkers, and the optimization strategies used for their rational design. Furthermore, we will discuss how factors like linker length, group type, flexibility, and linkage site affect the biodegradation efficiency of PROTACs. We believe that this work will contribute towards the advancement of rational linker design in the PROTAC research area. PROTAC represents a groundbreaking biotechnology in drug discovery. The characteristics of linker significantly impact the biodegradation efficiency of PROTAC, thereby governing the rational design of PROTAC. [Display omitted] [ABSTRACT FROM AUTHOR]

Toosendanin (TSN), a tetracyclic triterpenoid derived from Melia toosendan and M. azedarach , demonstrates broad application prospects in cancer treatment. Although previously employed as a pesticide, recent studies have revealed its potential therapeutic value in treating various types of cancer. TSN exerts an anticancer effect via mechanisms including proliferation inhibition, apoptosis induction, migration suppression, and angiogenesis inhibition. However, TSN's toxicity, particularly its hepatotoxicity, significantly limits its therapeutic application. This review explored the dual nature of TSN, evaluating both its anticancer potential and toxicological risks, emphasizing the importance of balancing these aspects in therapeutic applications. Furthermore, we investigated the incorporation of TSN into novel therapeutic strategies, such as Proteolysis-targeting chimeras (PROTAC) technology and nanotechnology-based drug delivery systems (DDS), which enhance treatment efficacy while mitigating toxicity in normal tissues. [ABSTRACT FROM AUTHOR]

An integrated platform was developed for NP-inspired PROTAC design, target identification and drug discovery. As a proof-of-concept study, this platform was applied to target characterization of 3-fluoro-10-hydroxylevodiamine, which highlighted the superiority of PROTAC technology in target identification of NPs and accelerated the process of NPs-based drug discovery. [Display omitted] • A new strategy combining PROTAC derivatization, quantitative proteomic analysis and binding affinity validation was developed for target identification and drug discovery of natural products. • The PROTAC-based target identitication strategy was successfully applied to characterize REXO4 as a direct target of 3-fluoro-10-hydroxylevodiamine. • Evodiamine-inspired PROTAC 13c showed potent antitumor activity and reduced toxic side effects through REXO4 degradation. Natural products (NPs) play a crucial role in the development of therapeutic drugs. However, it is still highly challenging to identify the targets of NPs. Besides, NPs usually exert their pharmacological activities via acting on multiple targets or pathways, which also poses great difficulties for the target identification of NPs. Inspired by our continuous efforts in designing drug-like protein degraders, this study introduced a successful example for the target identification and drug discovery of natural products evodiamine by employing PROTAC technology. Taking advantages of proteolysis targeting chimera (PROTAC), herein an integrated strategy combining PROTAC derivatization, quantitative proteomic analysis and binding affinity validation was developed for target identification and drug discovery of antitumor NP evodiamine. In this study, both highly potent PROTACs and negative controls were designed for quantitative proteomic analysis. Furthermore, REXO4 was confirmed as a direct target of 3-fluoro-10-hydroxylevodiamine, which induced cell death through ROS. In addition, the PROTAC 13c effectively degraded REXO4 both in vitro and in vivo , leading to potent antitumor activities and reduced toxic side effects. In summary, we developed an integrated strategy for the target identification and drug discovery of NPs, which was successfully applied to the PROTAC derivatization and target characterization of evodiamine. This proof-of-concept study highlighted the superiority of PROTAC technology in target identification of NPs and accelerated the process of NPs-based drug discovery, exhibiting broad application in NP-based drug development. [ABSTRACT FROM AUTHOR]

[Display omitted] Targeting oncogenic mutant p53 represents an attractive strategy for cancer treatment due to the high frequency of gain-of-function mutations and ectopic expression in various cancer types. Despite extensive efforts, the absence of a druggable active site for small molecules has rendered these mutants therapeutically non-actionable. Here we develop a selective and effective proteolysis-targeting chimera (PROTAC) for p53-R175H, a common hotspot mutant with dominant-negative and oncogenic activity. Using a novel iterative molecular docking-guided post-SELEX (systematic evolution of ligands by exponential enrichment) approach, we rationally engineer a high-performance DNA aptamer with improved affinity and specificity for p53-R175H. Leveraging this resulting aptamer as a binder for PROTACs, we successfully developed a selective p53-R175H degrader, named dp53m. dp53m induces the ubiquitin–proteasome-dependent degradation of p53-R175H while sparing wildtype p53. Importantly, dp53m demonstrates significant antitumor efficacy in p53-R175H-driven cancer cells both in vitro and in vivo , without toxicity. Moreover, dp53m significantly and synergistically improves the sensitivity of these cells to cisplatin, a commonly used chemotherapy drug. These findings provide evidence of the potential therapeutic value of dp53m in p53-R175H-driven cancers. [ABSTRACT FROM AUTHOR]

Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted, but are of great clinical significance. According to statistics, over 80% of disease-related pathogenic proteins cannot be targeted by current conventional treatment methods. In recent years, with the advancement of basic research and new technologies, the development of various new technologies and mechanisms has brought new perspectives to overcome challenging drug targets. Among them, targeted protein degradation technology is a breakthrough drug development strategy for challenging drug targets. This technology can specifically identify target proteins and directly degrade pathogenic target proteins by utilizing the inherent protein degradation pathways within cells. This new form of drug development includes various types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting chimera (AUTAC), autophagy-targeting chimera (AUTOTAC), degrader-antibody conjugate (DAC). This article systematically summarizes the application of targeted protein degradation technology in the development of degraders for challenging drug targets. Finally, the article looks forward to the future development direction and application prospects of targeted protein degradation technology. [ABSTRACT FROM AUTHOR]

The PWWP domain binds to both histone and DNA of a nucleosome in a bivalent way. PWWP domain-containing proteins are involved in different biological processes, and their aberrant expression is implicated in various human diseases. Here, we discuss the recent developments and challenges in targeting the PWWP domain for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017–2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders. This review summarizes the recent progress in the development of epigenetic degraders, including PROTACs, molecular glue, and hydrophobic tagging (HyT), with deep insights into the potential challenges and corresponding remedies. [Display omitted] [ABSTRACT FROM AUTHOR]

Targeted protein degradation (TPD), represented by proteolysis-targeting chimeras (PROTACs) and lysosome targeting chimeras (LYTACs), is a major breakthrough in drug discovery. LYTACs, designed to degrade extracellular proteins, provide a solution to the significant limitations of PROTACs, which are restricted to the degradation of intracellular proteins. New strategies that use various effectors to degrade extracellular proteins are promising, potentially signaling a new era in TPD. A comprehensive understanding of the new approaches for the degradation of extracellular proteins could accelerate advances in clinical applications. Targeted protein degradation (TPD) involving chimeric molecules has emerged as one of the most promising therapeutic modalities in recent years. Among various reported TPD strategies, proteolysis-targeting chimeras (PROTACs) stand out as a significant breakthrough in small-molecule drug discovery and have garnered the most attention to date. However, PROTACs are mainly capable of depleting intracellular proteins. Given that many important therapeutic targets such as cytokines, growth factors, and numerous receptors are membrane proteins or secreted extracellularly, there is interest in the development of novel strategies to degrade these protein categories. We review advances in this emerging area and provide insights to enhance the development of novel TPDs targeting extracellular proteins. [ABSTRACT FROM AUTHOR]

Aptamers offer immense promise for targeted protein degradation. Aptamer–PROTAC (proteolysis-targeting chimera) conjugates present an advantageous strategy to improve delivery efficiency, solubility, and permeability while mitigating off-tissue distribution-induced on-target toxicity. Aptamer-based PROTACs provide a feasible and promising platform for the spatiotemporal degradation of undruggable proteins. Aptamer-based lysosome-targeting chimeras (LYTACs) constitute a cost-effective alternative for the degradation of membrane-bound and extracellular proteins. Targeted protein degradation (TPD) technologies, particularly proteolysis-targeting chimeras (PROTACs), have emerged as a significant advancement in drug discovery. However, several hurdles – such as the difficulty of identifying suitable ligands for traditionally undruggable proteins, poor solubility and impermeability, nonspecific biodistribution, and on-target off-tissue toxicity – present challenges to their clinical applications. Aptamers are promising ligands for broad-ranging molecular recognition. Utilizing aptamers in TPD has shown potential advantages in overcoming these challenges. Here, we provide an overview of recent developments in aptamer-based TPD, emphasizing their potential to achieve targeted delivery and their promise for the spatiotemporal degradation of undruggable proteins. We also discuss the challenges and future directions of aptamer-based TPD with the goal of facilitating their clinical applications. [ABSTRACT FROM AUTHOR]

Targeted protein degradation (TPD) is an exciting new modality for inducing target protein destruction in cells by harnessing cellular degradation pathways. However, to develop effective and selective degraders with clinical potential, there are many challenges, ranging from developing an effective, tissue-penetrant, and selective degrader to understanding its mode of action. Integrating cutting-edge proteomic workflows during degrader development and application can overcome many challenges facing TPD. Chemoproteomics aids degrader development and refinement through dissection of ligand–protein interactions, ligandability of targets, degrader–target engagement, and specificity of binding. Quantitative proteomics aids TPD by delineating the specificity of protein-of-interest (POI) degradation, off-target effects of degraders, biological consequences of POI degradation, and mechanism of degradation. Technological advances in instrumentation, sample preparation workflows, and data-processing power are poised to enable proteomics approaches to be more effective and accessible for TPD applications. Targeted protein degradation (TPD) is an emerging modality for research and therapeutics. Most TPD approaches harness cellular ubiquitin-dependent proteolytic pathways. Proteolysis-targeting chimeras (PROTACs) and molecular glue (MG) degraders (MGDs) represent the most advanced TPD approaches, with some already used in clinical settings. Despite these advances, TPD still faces many challenges, pertaining to both the development of effective, selective, and tissue-penetrant degraders and understanding their mode of action. In this review, we focus on progress made in addressing these challenges. In particular, we discuss the utility and application of recent proteomic approaches as indispensable tools to enable insights into degrader development, including target engagement, degradation selectivity, efficacy, safety, and mode of action. [ABSTRACT FROM AUTHOR]

The ubiquitin–proteasome system (UPS) dedicates to degrade intracellular proteins to modulate demic homeostasis and functions of organisms. These enzymatic cascades mark and modifies target proteins diversly through covalently binding ubiquitin molecules. In the UPS, E3 ubiquitin ligases are the crucial constituents by the advantage of recognizing and presenting proteins to proteasomes for proteolysis. As the major regulators of protein homeostasis, E3 ligases are indispensable to proper cell manners in diverse systems, and they are well described in physiological bone growth and bone metabolism. Pathologically, classic bone-related diseases such as metabolic bone diseases, arthritis, bone neoplasms and bone metastasis of the tumor, etc., were also depicted in a UPS-dependent manner. Therefore, skeletal system is versatilely regulated by UPS and it is worthy to summarize the underlying mechanism. Furthermore, based on the current status of treatment, normal or pathological osteogenesis and tumorigenesis elaborated in this review highlight the clinical significance of UPS research. As a strategy possibly remedies the limitations of UPS treatment, emerging PROTAC was described comprehensively to illustrate its potential in clinical application. Altogether, the purpose of this review aims to provide more evidence for exploiting novel therapeutic strategies based on UPS for bone associated diseases. E3 ubiquitin ligases regulate bone homeostasis and pathological events variously. The UPS-dependent therapeutic significance of bone-associated diseases has been synthetically expatiated. [Display omitted] [ABSTRACT FROM AUTHOR]

Proteolysis-targeting chimera (PROTAC) is emerging as a new strategy to degrade target proteins in a precise way by taking advantage of the cellular ubiquitin-proteasome system. However, the potential cytotoxicity of PROTAC should be avoided to mitigate the off-target degradation of proteins in healthy tissues or cells. To address this issue, we herein present a strategy to cage a PROTAC with 4-(vinyloxy) benzyl carbonate (MZ1-O), which can be eliminated through a 3,6-dimethyl-1,2,4,5-tetrazine (Tz)-mediated inverse electron-demand Diels-Alder (iEDDA) reaction to generate a BRD4 (bromodomain-containing protein 4) degrader, MZ1. We further propose a dissolvable microneedle-assisted strategy for site-specific activation of MZ1-O that is delivered by a targeted delivery vector through systemic route in vivo , and demonstrate such a bioorthogonal strategy is efficient and precise for tumor treatment. Our study suggests that the bioorthogonal activation of PROTAC-based prodrug offers a highly specific and precise approach for cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Aurora kinase A (Aurora-A), a serine/threonine kinase, plays a pivotal role in various cellular processes, including mitotic entry, centrosome maturation and spindle formation. Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer, including lung cancer, colorectal cancer, and breast cancer. Alteration of Aurora-A impacts multiple cancer hallmarks, especially, immortalization, energy metabolism, immune escape and cell death resistance which are involved in cancer progression and resistance. This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance, including chemoresistance (taxanes, cisplatin, cyclophosphamide), targeted therapy resistance (osimertinib, imatinib, sorafenib, etc.), endocrine therapy resistance (tamoxifen, fulvestrant) and radioresistance. Specifically, the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair, feedback activation bypass pathways, resistance to apoptosis, necroptosis and autophagy, metastasis, and stemness. Noticeably, our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1 , ARID1A and MYC gene mutation tumors, and potential synergistic strategy for mTOR, PAK1, MDM2, MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase. In addition, we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment. This review highlights the most recent advances in Aurora-A-mediated cancer therapy resistance (chemoresistance, targeted therapy resistance, endocrine therapy resistance and radioresistance) and summarizes the synthetic lethality and combinational strategy for targeting Aurora-A kinase in precision medicine for cancer treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Dysregulation of histone deacetylases (HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has led to the approval of five HDAC inhibitors (HDACis). However, currently traditional HDACis, although effective in approved indications, exhibit severe off-target toxicities and low sensitivities against solid tumors, which have urged the development of next-generation of HDACi. This review investigates the biological functions of HDACs, the roles of HDACs in oncogenesis, the structural features of different HDAC isoforms, isoform-selective inhibitors, combination therapies, multitarget agents and HDAC PROTACs. We hope these data could inspire readers with new ideas to develop novel HDACi with good isoform selectivity, efficient anticancer effect, attenuated adverse effect and reduced drug resistance. The manuscript systematically reviews the biological functions of HDACs, the role of HDACs in oncogenesis, the structure features of different HDAC isoforms, isozyme-specific inhibitor, combination therapy, multitarget agent and HDAC PROTAC. [Display omitted] [ABSTRACT FROM AUTHOR]

PROteolysis Targeting Chimeras (PROTACs) have been extensively exploited for targeted protein degradation and cancer therapy. However, clinic translation of the conventional small molecular PROTACs is challenged by their unfavorable pharmacokinetic profiles and the systemic toxicity. This review overviewed the cutting-edge advance of stimuli-activatable PROTAC strategies for specific protein degradation in tumor cells and thereafter tumor regression. This review might provide novel insights for PROTAC-based precise protein degradation and cancer therapy. [Display omitted] The proteolysis targeting chimeras (PROTACs) approach has attracted extensive attention in the past decade, which represents an emerging therapeutic modality with the potential to tackle disease-causing proteins that are historically challengeable for conventional small molecular inhibitors. PROTAC harnesses the endogenic E3 ubiquitin ligase to degrade protein of interest (POI) via ubiquitin–proteasome system in a cycle-catalytic manner. The event-driven pharmacology of PROTAC is poised to pursue those targets that are conventionally undruggable, which enormously extends the space of drug development. Furthermore, PROTAC has the potential to address drug resistance of small molecular inhibitors by degrading the whole POI. Nevertheless, PROTACs display high-efficiency and always-on properties to degrade POI, they may cause severe side effects due to an "on-target but off-tissue" protein degradation profile at the undesirable tissues and cells. Given that, the stimuli-activatable PROTAC prodrugs have been recently exploited to confine precise protein degradation of the favorable targets, which may conquer the adverse effects of PROTAC due to uncontrollable protein degradation. Herein, we summarized the cutting-edge advances of the stimuli-activatable PROTAC prodrugs. We also overviewed the progress of PROTAC prodrug-based nanomedicine to improve PROTAC delivery to the tumors and precise POI degradation in the targeted cells. [ABSTRACT FROM AUTHOR]

We overview global clinical trials of targeted protein degradation (TPD) drugs for oncology across the past decade. The most common classes of TPD drugs in oncology clinical trials are selective estrogen receptor degraders (SERDs), immunomodulatory drugs (ImiDs), and proteolysis-targeting chimeras (PROTACs), all of which target protein degradation via the ubiquitin–proteasome system. Second-generation IMiDs with improved degradation potency could overcome resistance to lenalidomide and can treat more types of hematologic malignancies. The clinical development of oral SERDs still has many challenges, but several drugs have recently shown promising results in breast cancer patients with ESR1 mutations. Oral bioavailability and pharmacokinetics are two main issues that need to be addressed when developing clinically applicable PROTACs. Anticancer-targeted therapies inhibit various kinases implicated in cancer and have been used in clinical settings for decades. However, many cancer-related targets are proteins without catalytic activity and are difficult to target using traditional occupancy-driven inhibitors. Targeted protein degradation (TPD) is an emerging therapeutic modality that has expanded the druggable proteome for cancer treatment. With the entry of new-generation immunomodulatory drugs (IMiDs), selective estrogen receptor degraders (SERDs), and proteolysis-targeting chimera (PROTAC) drugs into clinical trials, the field of TPD has seen explosive growth in the past 10 years. Several challenges remain that need to be tackled to increase successful clinical translation of TPD drugs. We present an overview of the global landscape of clinical trials of TPD drugs over the past decade and summarize the clinical profiles of new-generation TPD drugs. In addition, we highlight the challenges and opportunities for the development of effective TPD drugs for future successful clinical translation. [ABSTRACT FROM AUTHOR]

Click chemistry has been proven to be very useful in drug delivery. Due to the availability of a large number of click reactions with a various characteristics, selection of appropriate chemistry for a given application is often not a trivial task. This review is written for pharmaceutical researchers who are interested in click chemistry applications and yet may not be click chemistry experts. For this, the review gives an overview of available click reactions organized by application types. Further, the general understanding of click reactions being fast and high yielding sometimes overshadows the need to analyze reaction kinetics in assessing suitability of a given reaction for certain applications. For this, we highlight the need to analyze the relationship among reaction kinetics, concentration effects, and reaction time scales, knowing that lack of such analysis could easily lead to failures. Further, possible issues such as chemical stability with various click reagents are also discussed to aid experimental designs. Recent examples and extensive references are also provided to aid in-depth understanding of technical details. We hope this review will help those interested in using click chemistry in drug delivery to select the appropriate reactions/reagents and minimize the number of pitfalls. Not all click reactions have the same fast reaction rate. Careful attention to reaction kinetics is needed in selecting appropriate reactions for a given application. [Display omitted] [ABSTRACT FROM AUTHOR]

Achieving tumor-specific protein loss remains a challenge in the delivery of proteolysis-targeting chimeras (PROTACs) as cancer therapeutics. As a solution, Wang et al. recently developed nanoformulated PROTACs (NAPs), a novel photoactivatable degradation approach. This innovative class of compounds harnesses near-infrared (NIR) light for precise PROTAC release and protein degradation in mouse tumors. [ABSTRACT FROM AUTHOR]

Despite numerous efforts to develop FGFR inhibitors for cancer treatment, the widespread clinical application of currently available FGFR inhibitors has been significantly limited due to the serious side effects caused by poor selectivity and resistance. PROTAC technology, a method for protein degradation, has shown notable advantages over conventional inhibitors. In our study, we coupled Erdafitinib , a pan-FGFR inhibitor, with a CRBN binder to synthesize and identify an effective FGFR2 degrader, N5. Our findings demonstrated that N5 displayed notable specificity for FGFR2 and outstanding enzyme inhibitory capabilities, achieving an IC 50 value of 0.08 nM against FGFR2, and strong antiproliferative activity, maintaining an inhibitory rate above 50% on gastric cancer cells at a concentration of 0.17 nM. Mechanistically, N5 induced gastric cancer cell cycle arrest at the G0/G1 phase and apoptosis by decreasing the levels of FGFR downstream proteins. Moreover, N5 demonstrated favorable pharmacokinetic characteristics with a bioavailability of 74.8% when administered intraperitoneally and effectively suppressed the growth of SNU16 xenograft tumors, exhibiting greater potency compared to the parental inhibitor Erdafitinib. This study lays the groundwork for developing and potentially applying therapeutic agents targeting FGFR2 degradation. [Display omitted] • N5 is a selective and effective FGFR2 degrader. • N5 is a high-affinity PROTAC with an IC 50 of 0.08 nM against FGFR2. • N5 induces G0/G1 cell cycle arrest and apoptosis in gastric cancer cells. • N5 presents favorable pharmacokinetic properties. • N5 is efficacious and well-tolerated in vivo. [ABSTRACT FROM AUTHOR]

Proteolysis targeting chimeras (PROTAC) are bifunctional chimeric molecules capable of directly degrading binding proteins through the ubiquitin-proteasome pathway. PROTACs have demonstrated significant potential in overcoming drug resistance and targeting previously untreatable targets. However, several limitations still need to be addressed, including their high molecular weight resulting in poor membrane permeability and bioavailability. In this study, we proposed that cancer-targeted penetrating peptides could enhance the cell permeability of PROTACs. We developed 26 novel targeted penetrating peptides for leukemia and lymphoma cells, among which C9C-f(3Bta) and Cyclo-C9C–R exhibited superior membrane permeability, targetability, and stability. By combining C9C-f(3Bta) and Cyclo-C9C–R with IMA-PROTAC, we effectively enhanced the anti-proliferative activity of IMA-PROTAC, facilitated degradation of Bcr-Abl protein in K562 cells, and reduced downstream STAT5 phosphorylation. Furthermore, the combined application promoted cell apoptosis while blocking G1 phase progression. HPLC-MRM-MS revealed that the combination of C9C-f(3Bta) or Cyclo-C9C–R with IMA-PROTAC significantly enhanced intracellular IMA-PROTAC content. In summary, our proof-of-concept study validated the hypothesis that combining PROTACs with targeted penetrating peptides can improve protein degradation efficiency as well as anti-proliferative capabilities. [Display omitted] • Designed and synthesized 26 novel human leukemia cells and lymphocyte cells targeted penetrating peptides. • These modified peptides had good permeability and targeting properties to K562 cells, KU812 cells and CCRF-CEM cells. • C9C-f(3Bta) or Cyclo-C9C–R had potent IMA-PROTAC co-application effects against K562 cells at low concentrations. • The combination of C9C-f(3Bta) or Cyclo-C9C–R with IMA-PROTAC can improve the degradation of Bcr-Abl protein. [ABSTRACT FROM AUTHOR]

[Display omitted] • Foxp3 targeting PROTACs were constructed using 15-mer peptide (P60). • P60-L3-VHL PROTAC degrade Foxp3 through the ubiquitin–proteasome pathway. • P60-L3-VHL inhibits Foxp3 expression and function in various cell types. • P60-L3-VHL has potential implications in cancer immunotherapy. Regulatory T (Treg) cells play a central role in immune homeostasis. Forkhead box P 3 (Foxp3), a hallmark molecule in Treg cells, is a vital transcription factor for their development and function. Studies have shown that degradation of the Foxp3 could provide therapeutic benefits in achieving effective anti-tumor immunity. In this study, we designed three PROTAC molecules, P60-L1-VHL, P60-L2-VHL, and P60-L3-VHL, based on a 15-mer peptide inhibitor of Foxp3 (P60), and explored their potential in regulating Foxp3 expression and function. Our data show that, among these molecules, P60-L3-VHL can inhibit the expression and nuclear localization of Foxp3 in HEK 293 T and HeLa cells, respectively. Meanwhile, use of proteasome inhibitor in P60-L3-VHL treated cells revealed an increased Foxp3 expression, indicating that P60-L3-VHL mediates the inhibition of Foxp3 through its degradation in the proteasome pathway. We further substantiate that P60-L3-VHL reduces the differentiation and Foxp3 expression in the in-vitro activated Treg cells. Overall, our findings suggest that P60-L3-VHL inhibits the differentiation of Treg cells by degrading the Foxp3, which may have potential implications in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Proteolysis-targeting chimeras (PROTACs), as heterobifunctional molecules, have garnered significant attention for their ability to target previously undruggable proteins. Due to the challenges in obtaining crystal structures of PROTAC molecules in the ternary complex, a plethora of computational tools have been developed to aid in PROTAC design. These computational tools can be broadly classified into artificial intelligence (AI)-based or non-AI-based methods. This review aims to provide a comprehensive overview of the latest computational methods for the PROTAC design process, covering both AI and non-AI approaches, from protein selection to ternary complex modeling and prediction. Key considerations for in silico PROTAC design are discussed, along with additional considerations for deploying AI-based models. These considerations are intended to guide subsequent model development in the PROTAC design process. Finally, future directions and recommendations are provided. [ABSTRACT FROM AUTHOR]

Drug development remains a critical focus within the global pharmaceutical industry. To date, more than 80 % of disease targets are considered difficult to target. The emergence of PROTAC technology has, to some extent, alleviated this challenge. Since introduction, PROTAC technology has evolved through the peptide E3 ligase ligand phase and the small molecule E3 ligase ligand phase. Currently, multiple PROTAC molecules are in the clinical research phase, showing promising potential for addressing drug resistance, disease recurrence, and intractable targets. Target deconvolution is a crucial step in the drug discovery and development process. Due to the exceptional targeting ability and specificity of PROTAC, it is widely used and promoted as an innovative technology for discovering new drug targets, leading to significant breakthroughs. The use of PROTAC probe requires only a catalytic dose and weak interaction with the target protein to achieve target degradation. Thus, it offers substantial advantages over traditional probes, particularly in identifying new targets that are low-abundance or difficult to target. This review provides a comprehensive overview of the advancements made by PROTAC technology in drug development and drug target discovery, while also systematically reviewing the workflow of PROTAC probe. With the ongoing development of PROTAC technology, PROTAC probe is poised to become a key research area in future drug target deconvolution. [Display omitted] • Proposed the concept of 'PROTAC Probe' and organized its technology workflow. • The milestones of PROTAC technology development are reviewed. • Novel PROTACs and the use of PROTAC technology in drug target deconvolution have been reviewed and sorted out. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase 7, along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs cell cycle progression via T-loop phosphorylation of cell cycle CDKs. Pharmacological inhibition of CDK7 leads to selective anti-cancer effects in cellular and in vivo models, motivating several ongoing clinical investigations of this target. Current CDK7 inhibitors are either reversible or covalent inhibitors of its catalytic activity. We hypothesized that small molecule targeted protein degradation (TPD) might result in differentiated pharmacology due to the loss of scaffolding functions. Here, we report the design and characterization of a potent CDK7 degrader that is comprised of an ATP-competitive CDK7 binder linked to a CRL2VHL recruiter. JWZ-5-13 effectively degrades CDK7 in multiple cancer cells and leads to a potent inhibition of cell proliferation. Additionally, compound JWZ-5-13 displayed bioavailability in a pharmacokinetic study conducted in mice. Therefore, JWZ-5-13 is a useful chemical probe to investigate the pharmacological consequences of CDK7 degradation. A potent and selective CDK7 degrader was developed. JWZ-5-13 induces a rapid and sustained CDK7 degradation and exhibits high proteome-wide selectivity. JWZ-5-13 displays advantages in inhibition of cancer cell proliferation over its parental binder and displays bioavailability in a pharmacokinetic study. [Display omitted] • JWZ-5-13 significantly degrades CDK7 in low nanomolar in multiple cell line. • JWZ-5-13 exhibits high proteome-wide selectivity. • JWZ-5-13 exhibited advantages in inhibition of cancer cell proliferation over its parental binder. • JWZ-5-13 displayed bioavailability in a pharmacokinetic study. [ABSTRACT FROM AUTHOR]

[Display omitted] • 19s is a potent and novel PAK1 degrader. • 19s exhibits potent anti-migration activity in vitro. • 19s induces rapid tumor regression in vivo. Triple-negative breast cancer is one of the most malignant subtypes in clinical practice, and it is urgent to find new therapies. The p21-activated kinase I (PAK1) has been considered to be an attractive therapeutic target for TNBC. In this study, we designed and synthesized a series of novel PROTAC PAK1 degraders by conjugating VHL or CRBN ligase ligands to PAK1 inhibitors which are connected by alkyl chains or PEG chains. The most promising compound, 19s , can significantly degrade PAK1 protein at concentrations as low as 0.1 μM, and achieves potent anti-proliferative activity with an IC 50 value of 1.27 μM in MDA-MB-231 cells. Additionally, 19s exhibits potent anti-migration activity in vitro and induces rapid tumor regression in vivo. Collectively, these findings document that 19s is a potent and novel PAK1 degrader with promising potential for TNBC treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • First extensive review on the synthesis and anti-cancer activity of (+)-JQ1 analogs are discussed. • SAR of the (+)-JQ1 scaffolds are also demonstrated. • Application of JQ1 scaffolds in PROTAC technology has been presented. • Mechanism of protein degradation by PROTACs are explained. • Challenges of PROTAC for medicinal chemists are also outlined. JQ1 is a wonder therapeutic molecule that selectively inhibits the BRD4 signaling pathway and is thus widely used in the anticancer drug discovery program. Due to its unique selective BRD4 binding property, its applications are further extended in the design and synthesis of bi-functional PROTAC molecules. This BRD4 targeting PROTAC molecule selectively degrades the protein by proteolysis. There are several modifications of JQ1 known to date and extensively explored for their applications in PROTAC technology by several research groups in academia as well as industry for targeting oncogenic genes. In this review, we have covered the discovery and synthesis of the JQ1 molecule. The SAR of the JQ1 analogs will help researchers develop potent JQ1 compounds with improved inhibitory properties against malignant cells. Furthermore, we explored the potential application of JQ1 analogs in PROTAC technology. The brief history of the bromodomain family of proteins, as well as the obstacles connected with PROTAC technology, can help comprehend the context of the current research, which has the potential to improve the drug development process. Overall, this review comprehensively appraises JQ1 molecules and their prior implementation in PROTAC technology and cancer therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Based on the 2-aminobenzamide derivative, a series of Vif PROTACs were synthesized. • L15 degrades Vif protein in a dose-dependent manner. • Mechanistic study confirmed L15 degrades Vif through ubiquitination pathway. • Molecular dynamics simulation confirmed the favorable binding of ternary complexes. Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin–proteasome system to degrade target proteins, which is well established in the field of cancer, but the antiviral PROTAC molecules are rarely reported. In order to explore the effectiveness of PROTAC in the antiviral area, we designed and synthesized a series of degrader of HIV-1 Vif based on 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold. Among them, L15 can degrade Vif protein obviously in a dose-dependent manner and shows certain antivirus activity. Meanwhile, molecular dynamics simulation indicated that the ternary complex formed by L15, Vif, and E3 ligase adopted a reasonable binding mode and maintained a stable interaction. This provided a molecular basis and prerequisite for the selective degradation of the Vif protein by L15. This study reports the HIV-1 Vif PROTAC for the first time and represents the proof-of-concept of PROTACs-based antiviral drug discovery in the field of HIV/ acquired immune deficiency syndrome (AIDS). [ABSTRACT FROM AUTHOR]

[Display omitted] Proteolysis targeting chimeras (PROTACs) are heterobifunctional small-molecule degraders made of a linker connecting a target-binding moiety to a ubiquitin E3 ligase-binding moiety. The linker unit is known to influence the physicochemical and pharmacokinetic properties of PROTACs, as well as the properties of ternary complexes, in turn impacting on their degradation activity in cells and in vivo. Our LRRK2 PROTAC XL01126, bearing a trans- cyclohexyl group in the linker, is a better and more cooperative degrader than its corresponding cis- analogue despite its much weaker binary binding affinities. Here, we investigate how this subtle stereocenter alteration in the linker affects the ligand binding affinity to the E3 ligase VHL. We designed a series of molecular matched pairs, truncating from the full PROTACs down to the VHL ligand, and find that across the series the trans -cyclohexyl compounds showed consistently weaker VHL-binding affinity compared to the cis- counterparts. High-resolution co-crystal structures revealed that the trans linker exhibits a rigid stick-out conformation, while the cis linker collapses into a folded-back conformation featuring a network of intramolecular contacts and long-range interactions with VHL. These observations are noteworthy as they reveal how a single stereochemical inversion within a PROTAC linker impacts conformational rigidity and binding mode, in turn fine-tuning differentiated propensity to binary and ternary complex formation, and ultimately cellular degradation activity. [ABSTRACT FROM AUTHOR]

The family of human-infecting coronaviruses (HCoVs) poses a serious threat to global health and includes several highly pathogenic strains that cause severe respiratory illnesses. It is essential that we develop effective broad-spectrum anti-HCoV agents to prepare for future outbreaks. In this study, we used PROteolysis TArgeting Chimera (PROTAC) technology focused on degradation of the HCoV main protease (Mpro), a conserved enzyme essential for viral replication and pathogenicity. By adapting the Mpro inhibitor GC376, we produced two novel PROTACs, P2 and P3 , which showed relatively broad-spectrum activity against the human-infecting CoVs HCoV-229E, HCoV-OC43, and SARS-CoV-2. The concentrations of these PROTACs that reduced virus replication by 50 % ranged from 0.71 to 4.6 μM, and neither showed cytotoxicity at 100 μM. Furthermore, mechanistic binding studies demonstrated that P2 and P3 effectively targeted HCoV-229E, HCoV-OC43, and SARS-CoV-2 by degrading Mpro within cells in vitro. This study highlights the potential of PROTAC technology in the development of broad-spectrum anti-HCoVs agents, presenting a novel approach for dealing with future viral outbreaks, particularly those stemming from CoVs. [Display omitted] • Modify GC376 at an activity-independent site to generate several PROTACs. • P2 and P3 showed activity against HCoV-229E, HCoV-OC43, and SARS-CoV-2. • P2 and P3 showed inhibition on SARS-CoV-2 Mpro. • P2 and P3 can bind both to Mpro and E3 ligase VHL, and induce degradation of SARS-CoV-2 Mpro in cells. [ABSTRACT FROM AUTHOR]

Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to the development and progression of multiple types of cancer. Although many FGFR inhibitors have been approved by the FDA, their long-term therapeutic efficacy is hampered by acquired resistance to gatekeeper mutations and low subtype selectivity. FGFR2 has been found to be frequently amplified or mutated in many tumors. In this study, we designed several PROTACs with different E3 ligands based on LY2874455. By screening the length of the linker and the binding site in various degraders, we obtained a novel and highly efficient FGFR2-selective degrader 28e (DC 50 = 0.645 nM, DC max = 86 %). Compound 28e selectively degraded FGFR2 and essentially avoided degradation of FGFR1,3,4 isoforms (DC 50 > 300 nM). Compound 28e significantly inhibited the proliferation of FGFR2-overexpressing cell lines, including KATOIII, SNU16, and AN3CA (IC 50 = 0.794 nM/0.207 nM/4.626 nM), comparable to parental inhibitors. At the same time, the preferred compound showed superiority over the parental inhibitor in kinase inhibitory activity against the gatekeeper mutant isoform FGFR2V564F (IC 50 = 0.121 nM). In summary, we identified 28e as a novel selective degrader of FGFR2 with high potency and high potential to overcome resistance to gatekeeper mutation. The discovery of 28e provides new evidence for the strategy of pan-inhibitor-based development of selective degrading agents. [Display omitted] • A series of novel FGFR2-selective degraders were designed and synthesized based on pan-FGFR inhibitor. • 28e exhibited the ability to efficiently degrade FGFR2 isoform with DC 50 of 0.645 nM. • 28e selectively degraded FGFR2 isoform but not FGFR1/3/4 isoforms. • 28e had the potential to overcome the FGFR2V564F gatekeeper resistance mutation. [ABSTRACT FROM AUTHOR]

[Display omitted] • This work first proved that momelotinib was a suitable warhead for the design of JAK1 PROTACs. • This work provides a new case study about JAK1 subtype-selective PROTACs. • Compound 10c may serve as a novel lead compound for antitumor drug discovery. • This work highlights the potential of JAK1-directed protein degradation as an antitumor therapeutic approach. Aberrant activation of the JAK-STAT pathway is evident in various human diseases including cancers. Proteolysis targeting chimeras (PROTACs) provide an attractive strategy for developing novel JAK-targeting drugs. Herein, a series of CRBN-directed JAK-targeting PROTACs were designed and synthesized utilizing a JAK1/JAK2 dual inhibitor—momelotinib as the warhead. The most promising compound 10c exhibited both good enzymatic potency and cellular antiproliferative effects. Western blot analysis revealed that compound 10c effectively and selectively degraded JAK1 in a proteasome-dependent manner (DC 50 = 214 nM). Moreover, PROTAC 10c significantly suppressed JAK1 and its key downstream signaling. Together, compound 10c may serve as a novel lead compound for antitumor drug discovery. [ABSTRACT FROM AUTHOR]

[Display omitted] • New A56 -based PROTACs target-degrading PD-L1 have been designed and synthesized. • Compounds 9i and 9j induce the internalization and degradation of PD-L1 in HCC-827 cells. • Compounds 9i and 9j degrade of PD-L1 through dual means of lysosome and proteasome. • The compounds have good anti-tumor activity by activating immunity in vivo. Currently, antibody drugs targeting programmed cell death ligand 1 (PD-L1) have achieved promising results in cancer treatment, while the development of small-molecule drugs lags behind. In this study, we designed and synthesized a series of PD-L1-degrading agents based on the PROTAC design principle, utilizing the PD-L1 inhibitor A56. Through systematic screening of ligands and linkers and investigating the structure–activity relationship of the degraders, we identified two highly active compounds, 9i and 9j. These compounds enhance levels of CD4+, CD8+, granzyme B, and perforin, demonstrating significant in vivo antitumor effects with a tumor growth inhibition (TGI) of up to 57.35 %. Both compounds facilitate the internalization of PD-L1 from the cell surface and promote its degradation through proteasomal and lysosomal pathways, while also maintaining inhibition of the PD-1/PD-L1 interaction. In summary, our findings provide a novel strategy and mechanism for developing biphenyl-based PROTAC antitumor drugs targeting and degrading PD-L1. [ABSTRACT FROM AUTHOR]

Macrophages play key roles in atherosclerosis progression, and an imbalance in M1/M2 macrophages leads to unstable plaques; therefore, M1/M2 macrophage polarization-targeted treatments may serve as a new approach in the treatment of atherosclerosis. At present, there is little research on M1/M2 macrophage polarization-targeted nanotechnology. Proteolysis-targeting chimera (PROTAC) technology, a targeted protein degradation technology, mediates the degradation of target proteins and has been widely promoted in preclinical and clinical applications as a novel therapeutic modality. This review summarizes the recent studies on M1/M2 macrophage polarization-targeted nanotechnology, focusing on the mechanism and advantages of PROTACs in M1/M2 macrophage polarization as a new approach for the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Nicotinamide phosphoribosyl transferase (NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation. However, therapeutic benefit of NAMPT enzymatic inhibitors appears very limited, likely due to the failure to intervene non-enzymatic functions of NAMPT. Herein, we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells (MDSCs) via a mechanism independent of its enzymatic activity. Using proteolysis-targeting chimera (PROTAC) technology, PROTAC A7 is identified as a potent and selective degrader of NAMPT, which degrades intracellular NAMPT (iNAMPT) via the ubiquitin–proteasome system, and in turn decreases the secretion of extracellular NAMPT (eNAMPT), the major player of the non-enzymatic activity of NAMPT. In vivo , PROTAC A7 efficiently degrades NAMPT, inhibits tumor infiltrating MDSCs, and boosts antitumor efficacy. Of note, the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on MDSCs. Together, our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment, and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT, pointing out a new direction for the development of NAMPT-targeted therapies. eNAMPT secreted from tumor cells suppresses antitumor immunity by promoting the expansion of tumor infiltrating MDSCs. NAMPT-specific PROTAC A7 directly degrades intracellular NAMPT, which in turn downregulates eNAMPT and promotes antitumor immunity. [Display omitted] [ABSTRACT FROM AUTHOR]

Accumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancers, either dependent or independent of its m6A methyl transferase activity. We have explored PROTACs targeting METTL3 and identified KH12 as a potent METTL3 degrader. Treatment of KH12 on MOLM-13 cells causes degradation of METTL3 with a DC 50 value of 220 nM in a dose-, time- and ubiquitin-dependent fashion. In addition, KH12 is capable of reversing differentiation and possesses anti-proliferative effects surpassing the small molecule inhibitors on MOLM-13 cells. Notably, we first present that METTL3 degrader significantly suppresses the growth of various gastric cancer (GC) cells, where the m6A-independent activity of METTL3 plays a crucial role in tumorigenesis. The anti-GC effects of KH12 were further confirmed in patient-derived organoids (PDOs). This study offers therapeutic potentials of targeted degradation of METTL3 against GC implicated with non-catalytic function of METTL3 as well as against AML. [Display omitted] • METTL3 PROTACs were synthesized and evaluated, leading to identification of KH12 as a potent VHL-based METTL3 degrader. • Mechanism of KH12 was assessed using ternary complex formation, target engagement, ubiquitination, and rescue experiments. • KH12 possesses higher anti-proliferative activities against AML cells compared to METTL3 inhibitors. • We first present that METTL3 degrader suppresses growth of gastric cancer cells, where METTL3 inhibitor has little effect. • The anti-GC effects of KH12 were further confirmed in GC patient-derived organoids (PDOs). [ABSTRACT FROM AUTHOR]

Proteolysis-Targeting Chimeras (PROTACs) are a novel class of bifunctional small molecules that alter protein levels by targeted degradation. This innovative approach uses the ubiquitin-proteasome system to selectively eradicate disease-associated proteins, providing a novel therapeutic strategy for a wide spectrum of diseases. This review delineates detailed synthetic approaches involved in PROTAC building blocks, including the ligand and protein binding parts, linker attached structural components of PROTACs and the actual PROTAC molecules. Furthermore, the recent advancements in PROTAC-mediated degradation of specific oncogenic and other disease-associated proteins, such as those involved in neurodegenerative, antiviral, and autoimmune diseases, were also discussed. Additionally, we described the current landscape of PROTAC clinical trials and highlighted key studies that underscore the translational potential of this emerging therapeutic modality. These findings demonstrate the versatility of PROTACs in modulating the levels of key proteins involved in various severe diseases. [Display omitted] • Toxic protein eradication with PROTAC is one of the most effective approaches to treating a range of serious illnesses. • This review provides an extensive summary of PROTAC synthesis methods and the latest advancements in PROTAC development. • The recent progress of PROTACs in clinical trials is highlighted. [ABSTRACT FROM AUTHOR]

Although anti-HER2 therapy has made significant strides in reducing metastasis and relapse in HER2-positive breast cancer, resistance to agents like trastuzumab, pertuzumab, and lapatinib frequently develops in patients undergoing treatment. Previous studies suggest that the hyperactivation of the PI3K-AKT signaling pathway by PIK3CA / PTEN gene mutations is implicated in HER2 resistance. In this study, we introduce a novel PI3K-p110α Proteolysis TAargeting Chimera (PROTAC) that effectively inhibits the proliferation of breast cancer cells by degrading PI3K-p110α. When tested in two lapatinib-resistant cell lines, JIMT1 and MDA-MB-453, both of which harbor PIK3CA mutations, the PI3K PROTAC notably reduced cell proliferation and induced G1 phase cell cycle arrest. Importantly, even at very low concentrations, PI3K PROTAC restored sensitivity to lapatinib. Furthermore, the efficacy of PI3K PROTAC surpassed that of Alpelisib, a selective PI3K-p110α kinase inhibitor in clinic. The superior performance of PI3K PROTAC was also confirmed in lapatinib-resistant breast cancer xenograft tumors and patient-derived breast cancer organoids (PDOs). In conclusion, this study reveals that the novel PI3K PROTAC we synthesized could serve as an effective agent to overcome lapatinib resistance. • Introducing a novel PI3K PROTAC that effectively overcomes resistance to HER2-targeted therapy. • Demonstrating the capability of the PI3K PROTAC to significantly enhance the sensitivity of lapatinib in HER2-positive breast cancer. • Establishing that the efficacy of the PI3K PROTAC surpasses that of Alpelisib specifically in HER2-positive breast cancer cell lines. [ABSTRACT FROM AUTHOR]

The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling. B cell malignancies which are dependent on the POU2F1/2 cofactor, POU2AF1, are also sensitive to mSWI/SNF ATPase degraders, with treatment leading to chromatin eviction of POU2AF1 and IRF4 and decreased IRF4 signaling in multiple myeloma cells. An orally bioavailable mSWI/SNF ATPase degrader significantly inhibits tumor growth in preclinical models of SCLC-P and multiple myeloma without signs of toxicity. This study suggests that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability. [Display omitted] • mSWI/SNF complex and its ATPase subunit are epigenetic dependencies in SCLC-P • POU2F3 complex requires the mSWI/SNF complex to modulate chromatin accessibility • POU2AF1 and IRF4 function as an epigenetic complex requiring mSWI/SNF in MM • An oral mSWI/SNF ATPase degrader shows potent anti-tumor efficacy in SCLC-P and MM He et al. reveal a promising avenue of treatment for small cell lung cancer and multiple myeloma driven by POU2F/POU2AF. The study highlights the potential of targeting the mSWI/SNF complex to impede oncogenic POU2F/POU2AF signaling and tumor growth, offering hope for improved therapies in these aggressive cancer types. [ABSTRACT FROM AUTHOR]

Proteolysis targeting chimeras (PROTACs) can use the intrinsic protein degradation system in cells to degrade pathogenic target proteins, and are currently a revolutionary frontier of development strategy for tumor treatment with small molecules. However, the poor water solubility, low cellular permeability, and off-target side effects of most PROTACs have prevented them from passing the preclinical research stage of drug development. This requires the use of appropriate delivery systems to overcome these challenging hurdles and ensure precise delivery of PROTACs towards the tumor site. Therefore, the combination of PROTACs and multifunctional delivery systems will open up new research directions for targeted degradation of tumor proteins. In this review, we systematically reviewed the design principles and the most recent advances of various PROTACs delivery systems. Moreover, the constructive strategies for developing multifunctional PROTACs delivery systems were proposed comprehensively. This review aims to deepen the understanding of PROTACs drugs and promote the further development of PROTACs delivery system. [ABSTRACT FROM AUTHOR]

[Display omitted] Oncogenic KRAS mutations drive an approximately 25 % of all human cancers. Son of Sevenless 1 (SOS1), a critical guanine nucleotide exchange factor, catalyzes the activation of KRAS. Targeting SOS1 degradation has engaged as a promising therapeutic strategy for KRAS-mutant cancers. Herein, we designed and synthesized a series of novel CRBN-recruiting SOS1 PROTACs using the pyrido[2,3- d ]pyrimidin-7-one-based SOS1 inhibitor as the warhead. One representative compound 11o effectively induced the degradation of SOS1 in three different KRAS-mutant cancer cell lines with DC 50 values ranging from 1.85 to 7.53 nM. Mechanism studies demonstrated that 11o -induced SOS1 degradation was dependent on CRBN and proteasome. Moreover, 11o inhibited the phosphorylation of ERK and displayed potent anti-proliferative activities against SW620, A549 and DLD-1 cells. Further optimization of 11o may provide us promising SOS1 degraders with favorable drug-like properties for developing new chemotherapies targeting KRAS-driven cancers. [ABSTRACT FROM AUTHOR]

[Display omitted] PROTACs (Proteolysis targeting chimeras) are chimeric molecules designed to induce targeted protein degradation via the ubiquitin–proteasome system. These molecules catalytically degrade target proteins and sustainably inhibit their function. Therefore, PROTAC's unique mechanism of action is not only beneficial in medicine but also serves as a valuable tool for molecular biological analysis in fields like chemical biology, biochemistry, and drug discovery. This study presents a novel turn-off (ON-OFF) type PROTAC development strategy utilizing a photocleavable linker. The inclusion of this linker enables temporal control of the degradation activity targeting BRD4 protein upon UV light exposure. PROTAC-2 demonstrated the most potent degradation activity against BRD4 among the other synthesized PROTACs with varying linker lengths. The UV light-induced cleavage of PROTAC-2 was confirmed, leading to a reduction in its BRD4 degradation activity. Notably, this study introduces a novel linker capable of nullifying degradation activity of PROTACs which is activated by light irradiation. These findings offer a promising strategy for the development of turn-off type PROTACs, providing enhanced temporal control over protein degradation. The approach holds significant potential for applications in molecular function studies and drug discovery. [ABSTRACT FROM AUTHOR]

The absence of effective active pockets makes traditional molecularly targeted drug strategies ineffective against 80 % of human disease-related proteins. The PROTAC technology effectively makes up for the deficiency of traditional molecular targeted drugs, which produces drug activity by degrading rather than inhibiting the target protein. The degradation of PROTAC is not only affected by POI ligand and E3 ligand, but by the selection of suitable linker which can play an important role in the efficiency and selectivity of the degradation. In the early exploring stage of the PROTAC, flexible chains were priorly applied as the linker of PROTAC. Although PROTAC with flexible chains as linkers sometimes perform well in vitro bioactivity evaluations, the introduction of lipophilic flexible chains reduces the hydrophilicity of these molecules, resulting in generally poor pharmacokinetic characteristics and pharmacological activities in vivo. In addition, recent reports have also shown that some PROTAC with flexible chains have some risks to causing hemolysis in vivo. Therefore, PROTAC with flexible chains show less druggability and large difficulty to entering the clinical trial stage. On the other hand, the application of nitrogen heterocycles in the design of PROTAC linkers has been widely reported in recent years. More and more reports have shown that the introduction of nitrogen heterocycles in the linker not only can effectively improves the metabolism of PROTAC in vivo , but also can enhance the degradation efficiency and selectivity of PROTAC. These PROTAC with nitrogen heterocycle linkers have attracted much attention of pharmaceutical chemists. The introduction of nitrogen heterocycles in the linker deserves priority consideration in the primary design of the PROTAC based on various druggabilities including pharmacokinetic characteristics and pharmacological activity. In this work, we summarized the optimization process and progress of nitrogen heterocyclic rings as the PROTAC linker in recent years. However, there were still limited understanding of how to discover, design and optimize PROTAC. For example, the selection of the types of nitrogen heterocycles and the optimization sites of this linker are challenges for researchers, choosing between four to six-membered nitrogen heterocycles, selecting from saturated to unsaturated ones, and even optimizing the length and extension angle of the linker. There is a truly need for theoretical explanation and elucidation of the PROTAC to guide the developing of more effective and valuable PROTAC. [Display omitted] • Nitrogen heterocycles, such as triazoles, saturated variants, and azaspiros, widely applying in PROTAC linkers. • Nitrogen heterocycles in PROTAC linkers critically affecting degradation activity, selectivity, and pharmacokinetics. • Key considerations of Nitrogen heterocycles in PROTAC linker including heterocycle type, quantity, chirality, and their binding specificity. [ABSTRACT FROM AUTHOR]

The revolutionary Proteolysis Targeting Chimera (PROTACs) have the exciting potential to reshape the pharmaceutical industry landscape by leveraging the ubiquitin-proteasome system for targeted protein degradation. Breast cancer, the most prevalent cancer in women, could be treated using PROTAC therapy. Although substantial work has been conducted, there is not yet a comprehensive overview or progress update on PROTAC therapy for breast cancer. Hence, in this article, we've compiled recent research progress focusing on different breast cancer target proteins, such as estrogen receptor (ER), BET, CDK, HER2, PARP, EZH2, etc. This resource aims to serve as a guide for future PROTAC-based breast cancer treatment design. [Display omitted] [ABSTRACT FROM AUTHOR]

• E3 ligase significantly impacts PROTAC effectiveness. • The optimal ligand can vary depending on the target kinase. • Factors such as subcellular localization, expression levels and physiological roles of E3 ligases can be used for making efficient and selective PROTACs. Proteolysis targeting chimera (PROTACs) provide a novel therapeutic approach that is revolutionizing drug discovery. The success of PROTACs largely depends on the combination of their three fragments: E3 ligase ligand, linker and protein of interest (POI)-targeting ligand. We summarize the pivotal significance of the precise combination of the E3 ligase ligand with the POI-recruiting warhead, which is crucial for the successful execution of cellular processes and achieving the desired outcomes. Therefore, the key to our selection was the use of at least two ligands recruiting two different ligases. This approach enables a direct comparison of the impacts of the specific ligases on target degradation. [ABSTRACT FROM AUTHOR]

MDM2 genes amplification or altered expression is commonly observed in various cancers bearing wild-type TP53. Directly targeting the p53-binding pocket of MDM2 to activate the p53 pathway represents a promising therapeutic approach. Despite the development of numerous potent MDM2 inhibitors that have advanced into clinical trials, their utility is frequently hampered by drug resistance and hematologic toxicity such as neutropenia and thrombocytopenia. The emergence of PROTAC technology has revolutionized drug discovery and development, with applications in both preclinical and clinical research. Harnessing the power of PROTAC molecules to achieve MDM2 targeted degradation and p53 reactivation holds significant promise for cancer therapy. In this review, we summarize representative MDM2 PROTAC degraders and provide insights for researchers investigating MDM2 proteins and the p53 pathway. [Display omitted] • The clinical application of MDM2 inhibitors may be limited by several side effects and drug resistance. • MDM2 PROTAC degraders offer promising prospects for cancer therapy. • This review provides a comprehensive summary of recent progress in the development of MDM2 PROTACs. • KT-253, a pioneering MDM2 PROTAC, has entered phase I clinical trial, a significant milestone in cancer treatment research. [ABSTRACT FROM AUTHOR]

Epigenetic alterations promote cancer development by regulating the expression of various oncogenes and anti-oncogenes. Histone methylation modification represents a pivotal area in epigenetic research and numerous publications have demonstrated that aberrant histone methylation is highly correlated with tumorigenesis and development. As a key histone demethylase, lysine-specific demethylase 5B (KDM5B) demethylates lysine 4 of histone 3 (H3K4) and serves as a transcriptional repressor of certain tumor suppressor genes. Meanwhile, KDM5B inhibits STING-induced intrinsic immune response of tumor cells or recruits SETDB1 through non-enzymatic function to silence reverse transcription elements to promote immune escape. The conventional small molecule inhibitors can only inhibit the enzymatic function of KDM5B with no effect on the non-enzymatic function. In the article, we present the development of the first series of KDM5B degraders based on CPI-455 to inhibit the non-enzymatic function. Among them, GT-653 showed optimal KDM5B degradation efficiency in a ubiquitin proteasome-dependent manner. GT-653 efficiently reduced KDM5B protein levels without affecting KDM5B transcription. Interestingly, GT-653 increased H3K4me3 levels and activated the type-I interferon signaling pathway in 22RV1 cells without significant phenotypic response on cell proliferation. [Display omitted] • Discovery of an effective KDM5B degrader. • GT-653 induced KDM5B degradation via PROTAC mechanism. • GT-653 treatment activates the type-I interferon signaling pathway. [ABSTRACT FROM AUTHOR]

Although three generations of Epidermal growth factor receptor (EGFR) - TK inhibitors have been approved for the treatment of Non-small-cell lung cancers (NSCLC), their clinical application is still largely hindered by acquired drug resistance mediated new EGFR mutations and side effects. The Proteolysis targeting chimera (PROTAC) technology has the potential to overcome acquired resistance from mutant EGFR through a novel mechanism of action. In this study, we developed the candidate degrader IV-3 by structural modifications of the lead compound 13 , which exhibited limited antiproliferative activity against HCC-827 cells. Compared to compound 13 , IV-3 exhibited remarkable anti-proliferative activity against HCC-827 cells, NCI–H1975 cells, and NCI–H1975-TM cells (IC 50 = 0.009 μM, 0.49 μM and 3.24 μM, respectively), as well as significantly inducing degradation of EGFR protein in these cell lines (DC 50 = 17.93 nM, 0.25 μM and 0.63 μM, respectively). Further investigations confirmed that IV-3 exhibited superior anti-tumor activity in all xenograft tumor models through the degradation of mutant EGFR protein. Moreover, IV-3 showed no inhibitory activity against A431 and A549 cells expressing wild-type EGFR, thereby eliminating potential toxic side effects emerging from wild-type EGFR inhibition. Overall, our study provides promising insights into EGFR-PROTACs as a potential therapeutic strategy against EGFR-acquired mutation. [Display omitted] • IV-3 significantly induced EGFR protein degradation in various EGFR mutant cell lines. • IV-3 promoted the sustained degradation of EGFR via the ubiquitin-proteasome system. • IV-3 demonstrated reasonable PK profiles and superior in vivo efficacy. • Providing promising insights for the development of EGFR degraders. [ABSTRACT FROM AUTHOR]