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High-grade B-cell lymphoma with translocations involving MYC and BCL2 or BCL6, usually referred to as double hit lymphoma (DHL), is an aggressive hematological malignance with distinct genetic features and poor clinical prognosis. Current standard chemoimmunotherapy fails to confer satisfying outcomes and few targeted therapeutics are available for the treatment against DHL. Recently, the delineating of the genetic landscape in tumors has provided insight into both biology and targeted therapies. Therefore, it is essential to understand the altered signaling pathways of DHL to develop treatment strategies with better clinical benefits. Herein, we summarized the genetic alterations in the two DHL subtypes (DHL-BCL2 and DHL-BCL6). We further elucidate their implications on cellular processes, including anti-apoptosis, epigenetic regulations, B-cell receptor signaling, and immune escape. Ongoing and potential therapeutic strategies and targeted drugs steered by these alterations were reviewed accordingly. Based on these findings, we also discuss the therapeutic vulnerabilities that coincide with these genetic changes. We believe that the understanding of the DHL studies will provide insight into this disease and capacitate the finding of more effective treatment strategies. [ABSTRACT FROM AUTHOR]

A series of pyrazole-thiophene derivatives exhibiting good Akt inhibitory activities were obtained on the basis of conformational restriction strategy, leading to the discovery of compound 1d and 1o which showed excellent in vitro antitumor effect against a variety of hematologic cancer cells and their potential of inducing apoptosis, blocking the cell cycles at S phase and significantly inhibiting the phosphorylation of downstream biomarkers of Akt kinase of cancer cells. Amongst, compound 1o also exhibited good PK profiles and inhibited about 40% tumor growth in MM1S xenograft model. Compound 1o might be a potential candidate for further development. Image 1 • Compound 1d and 1o with good Akt inhibitory activities were obtained on the basis of conformational restriction strategy. • Compound 1d and 1o showed excellent in vitro antitumor effect. • Compound 1o exhibited good PK profiles and a 40% tumor growth inhibition in MM1S xenograft tumor model. [ABSTRACT FROM AUTHOR]

A series of furan/thiophene-derived Cr-MIL-101s were obtained via visible-light-mediated C–C bond-forming catalysis within photosensitizing porous materials. The guest trapping process was achieved under very mild and metal-free conditions, affording newly functionalized MOFs with more π–π stacking, hydrogen bonding properties and excellent adsorption capacity in removing herbicides from aquatic environments. [ABSTRACT FROM AUTHOR]

The M2 polarized macrophages modulation has been described as a beneficial approach to facilitate the myelin repairing and inflammation microenvironment remodeling of multiple sclerosis (MS). Whereas, the M2 polarization involves complex mechanisms, and the modulators are still limited. As a protein kinase B (Akt) inhibitor, compound 2 was found promoting M2 polarization activity in our previous research, here we report the identification of a new modulator B9 with high M2-marker Arg 1 upregulation activity, M1 polarization inhibition and ablated Akt1 inhibition activities. B9 has promising pharmacokinetic profiles, and significantly ameliorates the symptom and reduces demyelination in EAE mice. Moreover, the inflammation microenvironment is remodeled after B9 administration, with promoted M2-type macrophages and inhibited M1 polarization in the CNS and periphery, and suppressed the proinflammatory Th1 and Th17 cells responses. Therefore, the new macrophage M2 polarization modulator B9 could present a candidate for fulfilling the therapeutic strategies of MS. [Display omitted] • A new modulator B9 with high macrophage M2 polarization activity was identified. • Compound B9 showed ablated Akt1 inhibition activity based on rational design. • B9 significantly ameliorated the symptom and reduced demyelination in EAE mice. • The inflammation microenvironment was remodeled after B9 administration. [ABSTRACT FROM AUTHOR]

Modulating the glucose transport in skeletal muscle is a promising strategy for ameliorating glucose homeostasis disorders. However, the complicated mechanisms of glucose transport make it difficult to find compounds therapeutically relevant molecular mechanisms of action, while phenotypic screening is thought to be an alternative approach to mimic the cell state of interest. Here, we report (±)-seneciobipyrrolidine (1a) is first found to enhance glucose uptake in L6 myotubes through phenotype-based screening. Further SAR investigation led to the identfication of compound A27 (EC 50 = 2.7 μM). Proteomiic analysis discloses the unique function mechanism of A27 through upregulating the level of the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), subsequently enhancing the Akt and AMPK phosphorylation, thereby promoting the glucose uptake. Chronic oral administration of A27 significantly lowers blood glucose and improves glucose tolerance in db/db mice. This work is new research on seneciobipyrrolidine derivatives, providing a promising avenue for ameliorating glucose homeostasis. [Display omitted] • (±)-Seneciobipyrrolidine is first found to enhance glucose uptake in L6 myotubes. • The octahydro-dipyrrolo-quinoline derivatives show potent antidiabetic activity. • Compound A27 may function through activating 4E-BP1/Akt/AMPK signaling. [ABSTRACT FROM AUTHOR]

• Myrcene stimulates the spore germination of Penicillium digitatum. • Myrcene accelerate the initiation of green mold. • Myrcene up-regulates the carbon and energy metabolism of P. digitatum spores. Tremendous economic losses in the citrus industry are caused by infestations of Penicillium digitatum. Previous research has shown that the terpene myrcene in citrus essential oils could stimulate the spore germination and mycelial growth of P. digitatum. However, the underlying mechanism is poorly known. Here, how myrcene induces the spore germination of P. digitatum was elucidated. The addition of myrcene significantly promoted the spore germination of P. digitatum and green mold in citrus fruit. As the incubation time increased, the intracellular and extracellular myrcene contents both significantly decreased in myrcene-treated samples, and no downstream products were detected through a Gas Chromatography-Mass Spectrometer. Metabolomics analysis revealed that the contents of metabolites involved in central carbon metabolism, such as glycolysis, pentose phosphate pathway, and citrate cycle, were significantly affected after the addition of myrcene. The adenosine triphosphate content and the intracellular energy charge were also drastically increased. Overall, our results suggest that the ability of myrcene to stimulate the spore germination of P. digitatum might be mediated by the upregulation of central carbon and energy metabolism. [ABSTRACT FROM AUTHOR]

The enzymes involved in the metabolic pathways in cancer cells have been demonstrated as important therapeutic targets such as the isocitrate dehydrogenase 2 (IDH2). A series of macrocyclic derivatives was designed based on the marketed IDH2 inhibitor AG-221 by using the conformational restriction strategy. The resulted compounds showed moderate to good inhibitory potential against different IDH2-mutant enzymes. Amongst, compound C6 exhibited better IDH2R140Q inhibitory potency than AG-221 , and showed excellent activity of 2-hydroxyglutarate (2-HG) suppression in vitro and its mesylate displayed good pharmacokinetic profiles. Moreover, C6 performed strong binding mode to IDH2R140Q after computational docking and dynamic simulation, which may serve as a good starting point for further development. Image 1 • A series of macrocyclic inhibitors targeting mutant IDH2 was designed by using the conformational restriction strategy. • Compound C6 exhibited better IDH2R140Q inhibitory potency than AG-221. • Compound C6 performed strong binding mode to IDHR140Q after computational docking and dynamic simulation. [ABSTRACT FROM AUTHOR]

Immune suppression in the tumor microenvironment (TME) is an intractable issue in anti-cancer immunotherapy. The chemokine receptors CXCR1 and CXCR2 recruit immune suppressive cells such as the myeloid derived suppressor cells (MDSCs) to the TME. Therefore, CXCR1/2 antagonists have aroused pharmaceutical interest in recent years. In this review, the medicinal chemistry of CXCR1/2 antagonists and their relevance in cancer immunotherapy have been summarized. The development of the drug candidates, along with their design rationale, clinical status and current challenges have also been discussed. Image 1 • CXCR1/2 was considered as pivot of recruiting immune suppressive cells to tumor microenvironment. • This review gave an effort along with the classification and SAR discussion of reported CXCR2 antagonists. • The relevance between CXCR2 and cancer immunosuppressive cells such as MDSCs was discussed. [ABSTRACT FROM AUTHOR]

Bystander‐killing payloads can significantly overcome the tumor heterogeneity issue and enhance the clinical potential of antibody‐drug conjugates (ADC), but the rational design and identification of effective bystander warheads constrain the broader implementation of this strategy. Here, graph attention networks (GAT) are constructed for a rational bystander killing scoring model and ADC construction workflow for the first time. To generate efficient bystander‐killing payloads, this model is utilized for score‐directed exatecan derivatives design. Among them, Ed9, the most potent payload with satisfactory permeability and bioactivity, is further used to construct ADC. Through linker optimization and conjugation, novel ADCs are constructed that perform excellent anti‐tumor efficacy and bystander‐killing effect in vivo and in vitro. The optimal conjugate T‐VEd9 exhibited therapeutic efficacy superior to DS‐8201 against heterogeneous tumors. These results demonstrate that the effective scoring approach can pave the way for the discovery of novel ADC with promising bystander payloads to combat tumor heterogeneity. [ABSTRACT FROM AUTHOR]

Predicting the biological properties of molecules is crucial in computer-aided drug development, yet it's often impeded by data scarcity and imbalance in many practical applications. Existing approaches are based on self-supervised learning or 3D data and using an increasing number of parameters to improve performance. These approaches may not take full advantage of established chemical knowledge and could inadvertently introduce noise into the respective model. In this study, we introduce a more elegant transformer-based framework with focused attention for molecular representation (TransFoxMol) to improve the understanding of artificial intelligence (AI) of molecular structure property relationships. TransFoxMol incorporates a multi-scale 2D molecular environment into a graph neural network + Transformer module and uses prior chemical maps to obtain a more focused attention landscape compared to that obtained using existing approaches. Experimental results show that TransFoxMol achieves state-of-the-art performance on MoleculeNet benchmarks and surpasses the performance of baselines that use self-supervised learning or geometry-enhanced strategies on small-scale datasets. Subsequent analyses indicate that TransFoxMol's predictions are highly interpretable and the clever use of chemical knowledge enables AI to perceive molecules in a simple but rational way, enhancing performance. [ABSTRACT FROM AUTHOR]

Molecular clustering analysis has been developed to facilitate visual inspection in the process of structure-based virtual screening. However, traditional methods based on molecular fingerprints or molecular descriptors limit the accuracy of selecting active hit compounds, which may be attributed to the lack of representations of receptor structural and protein–ligand interaction during the clustering. Here, a novel deep clustering framework named ClusterX is proposed to learn molecular representations of protein–ligand complexes and cluster the ligands. In ClusterX, the graph was used to represent the protein–ligand complex, and the joint optimisation can be used efficiently for learning the cluster-friendly features. Experiments on the KLIFs database show that the model can distinguish well between the binding modes of different kinase inhibitors. To validate the effectiveness of the model, the clustering results on the virtual screening dataset further demonstrated that ClusterX achieved better or more competitive performance against traditional methods, such as SIFt and extended connectivity fingerprints. This framework may provide a unique tool for clustering analysis and prove to assist computational medicinal chemists in visual decision-making. [ABSTRACT FROM AUTHOR]

High expression of ubiquitin-specific protease 10 (USP10) promote the proliferation of hepatocellular carcinoma (HCC), thus the development of USP10 inhibitors holds promise as a novel therapeutic approach for HCC treatment. However, the development of selective USP10 inhibitor is still limited. In this study, we developed a novel USP10 inhibitor for investigating the feasibility of targeting USP10 for the treatment of HCC. Due to high USP10 inhibition potency and prominent selectivity, compound D1 bearing quinolin-4(1 H)-one scaffold was identified as a lead compound. Subsequent research revealed that D1 significantly inhibits cell proliferation and clone formation in HCC cells. Mechanistic insights indicated that D1 targets the ubiquitin pathway, facilitating the degradation of YAP (Yes-associated protein), thereby triggering the downregulation of p53 and its downstream protein p21. Ultimately, this cascade leads to S-phase arrest in HCC cells, followed by cell apoptosis. Collectively, our findings highlight D1 as a promising starting point for USP10-positive HCC treatment, underscoring its potential as a vital tool for unraveling the functional intricacies of USP10. [Display omitted] • A series of quinolin-4(1 H)-one derivatives targeting USP10 was identified through protein structure prediction and virtual screening. • Compound D1 exhibited strong USP10 inhibition and promising selectivity against USP7. • Compound D1 could promote YAP degradation and inhibit the proliferation of HCC cells. [ABSTRACT FROM AUTHOR]

Nuclear export protein 1 (XPO1), a member of the nuclear export protein-p (Karyopherin-P) superfamily, regulates the transport of "cargo" proteins. To facilitate this important process, which is essential for cellular homeostasis, XPO1 must first recognize and bind the cargo proteins. To inhibit this process, small molecule inhibitors have been designed that inhibit XPO1 activity through covalent binding. However, the scaffolds for these inhibitors are very limited. While virtual screening may be used to expand the diversity of the XPO1 inhibitor skeleton, enormous computational resources would be required to accomplish this using traditional screening methods. In the present study, we report the development of a hybrid virtual screening workflow and its application in XPO1 covalent inhibitor screening. After screening, several promising XPO1 covalent molecules were obtained. Of these, compound 8 performed well in both tumor cell proliferation assays and a nuclear export inhibition assay. In addition, molecular dynamics simulations were performed to provide information on the mode of interaction of compound 8 with XPO1. This research has identified a promising new scaffold for XPO1 inhibitors, and it demonstrates an effective and resource-saving workflow for identifying new covalent inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: A set of forty-seven Akt1 inhibitors was used for the development of molecular docking based QSAR model by using nonlinear regression. The integration of docking scores, key interaction profiles and molecular descriptors remarkably improved the accuracy of the QSAR models, providing reasonable statistical parameters (R train 2 = 0.948, R test 2 = 0.907 and Q cv 2 = 0.794). The established MD-SVR model based structural modification of new 4-amino-pyrimidine derivatives was further performed, and six compounds 56a,b and 60a–d with good prediction activities were synthesized and biologically evaluated. All of these compounds exhibited promising Akt1 inhibitory and antiproliferative activities, suggesting the reliability and good application value of the established MD-SVR model in the development of Akt1 inhibitors. [Copyright &y& Elsevier]

The potential for secondary stroke prevention, which can significantly reduce the risk of recurrent strokes by almost 90%, underscores its critical importance. N-butylphthalide (NBP) has emerged as a promising treatment for acute cerebral ischemia, yet its efficacy for secondary stroke prevention is hindered by inadequate pharmacokinetic properties. This study, driven by a comprehensive structural analysis, the iterative process of structure optimization culminated in the identification of compound B4 , which demonstrated exceptional neuroprotective efficacy and remarkable oral exposure and oral bioavailability. Notably, in an in vivo transient middle cerebral artery occlusion (tMCAO) model, B4 substantially attenuated infarct volumes, surpassing the effectiveness of NBP. While oral treatment with B4 exhibited stronger prevention potency than NBP in photothrombotic (PT) model. In summary, compound B4 , with its impressive oral bioavailability and potent neuroprotective effects, offers promise for both acute ischemic stroke treatment and secondary stroke prevention. [Display omitted] • A series of novel phenyltetrazolium derivatives were designed and synthesized. • Among 18 synthesized compounds, compound B4 exhibited strongest cell protective potency and oral exposure. • Compound B4 inhibited stroke both in tMCAO model and PT model. [ABSTRACT FROM AUTHOR]

AML is an aggressive malignancy of immature myeloid progenitor cells. Discovering effective treatments for AML through cell differentiation and anti-proliferation remains a significant challenge. Building on previous studies on CDK2 PROTACs with differentiation-inducing properties, this research aims to enhance CDKs degradation through structural optimization to facilitate the differentiation and inhibit the proliferation of AML cells. Compound C3 , featuring a 4-methylpiperidine ring linker, effectively degraded CDK2 with a DC 50 value of 18.73 ± 10.78 nM, and stimulated 72.77 ± 3.51 % cell differentiation at 6.25 nM in HL-60 cells. Moreover, C3 exhibited potent anti-proliferative activity against various AML cell types. Degradation selectivity analysis indicated that C3 could be endowed with efficient degradation of CDK2/4/6/9 and FLT3, especially FLT3-ITD in MV4-11 cells. These findings propose that C3 combined targeting CDK2/4/6/9 and FLT3 with enhanced differentiation and proliferation inhibition, which holds promise as a potential treatment for AML. [Display omitted] • • C3 degrades CDK2 with DC 50 value of 18.73 ± 10.78 nM, and D max of 86.83 ± 8.75 %. • • C3 notably reduced the protein levels of CDK4/6/9 and FLT3 in AML cell lines. • • The pro-differentiation effect of C3 was 72.77 ± 3.51 % at 6.25 nM on day 5. • • C3 exhibited anti-proliferative activity in MV4-11 with IC 50 = 2.90 ± 0.14 nM. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (AMI) patients are at an elevated risk for life-threatening myocardial ischemia/reperfusion injury. Early-stage nonradioactive and noninvasive diagnosis of AMI is imperative for the subsequent disease treatment, yet it presents substantial challenges. After AMI, the myocardium typically exhibits elevated levels of peroxynitrite (ONOO−), constituting a distinct microenvironmental feature. In this context, the near-infrared imaging probe (BBEB) is employed to precisely delineate the boundaries of AMI lesions with a high level of sensitivity and specificity by monitoring endogenous ONOO−. This probe allows for the early detection of myocardial damage at cellular and animal levels, providing exceptional temporal and spatial resolution. Notably, BBEB enables visualization of ONOO− level alterations during AMI treatment incorporating antioxidant drugs. Overall, BBEB can rapidly and accurately visualize myocardial injury, particularly in the early stages, and can further facilitate antioxidant drug screening. [Display omitted] • We have developed a novel fluorescent probe called BBEB for the detection of ONOO−. • BBEB can detect the dynamic change of ONOO− in living cells. • Using BBEB enables the visualization of early myocardial injury at both the cellular and animal levels. • BBEB can accurately identify the boundaries of myocardial damage. • BBEB is a valuable tool for screening antioxidant drugs. [ABSTRACT FROM AUTHOR]

Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase in the MAP4K family, is expressed predominantly in immune cells, and has been identified as a negative regulator of immune signaling. Accumulating evidences demonstrated that loss of HPK1 kinase function effectively enhances anti-tumor responses. In this study, we disclose the medicinal chemistry campaigns to discovery potent, selective, and orally active HPK1 inhibitors, starting from our previous work based on rigidification strategy. Systematically structure-activity relationship (SAR) exploration led to the identification of F03 (HMC-B17). The representative compound, HMC-B17 , showed the potent HPK1 inhibition with an IC 50 value of 1.39 nM and favorable selectivity against TCR-related kinases. In addition, the HMC-B17 effectively enhanced the IL-2 secretion in Jurkat cells (EC 50 = 11.56 nM). Strikingly, immune-reverse effects and improved immune response in vivo were observed after HMC-B17 treatment. Furthermore, HMC-B17 combined with anti -PD-L1 antibody demonstrated a synergistic antitumor efficacy with TGI% value of 71.24 % in CT26 model. Collectively, our findings suggest that HMC-B17 could be a valuable lead compound to develop a safe and potent HPK1 inhibitor for further cancer immunotherapy. [Display omitted] • Highly TCR-related kinases selectivity is critical for the success of HPK1 drug discovery. • In this study, systematically SAR explorations were performed, and compound HMC-B17 was identified as a novel, potent, selective and orally bioavailable HPK1 inhibitor. • HMC-B17 showed a synergistic antitumor efficacy with TGI% value of 71.24 % in CT26 model when combined with anti -PD-L1 antibody. • Compound HMC-B17 is a promising chemical entity, which deserves further investigation in cancer immunotherapy filed. [ABSTRACT FROM AUTHOR]

The emergence of imazalil (IMZ) resistance in Penicillium digitatum has become a great threat for controlling citrus green mold. In this paper, we investigated the antifungal efficiency and mechanism of an alkaloid antofine against an IMZ‐resistant P. digitatum strain Pdw03. Results showed that antofine exhibited a strong antifungal activity against the mycelial growth of strain Pdw03, with a minimum inhibitory concentration (MIC) and the minimum fungicidal concentration (MFC) of 1.56 × 10−3 and 1.25 × 10−2 g/L, respectively. In vivo application of antofine effectively delayed the disease progress and reduced the incidence of green mold in citrus fruit. The disease incidence of 10 × MFC antofine‐treated fruit after 6 days of storage was only 11% ± 4%, which was significantly lower than that of the control (100% ± 0%). Antofine treatment altered mycelial morphology of strain Pdw03 without affecting the cell wall integrity. Although the ergosterol contents remained stable, a decrease in the total lipid content induced by lipid peroxidation was observed at 30 min of exposure, indicating disruption of cell membrane permeability of strain Pdw03. In addition, the mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) contents were also decreased at 60 min of exposure. These results indicated that antofine inhibited the growth of strain Pdw03 by disrupting cell membrane permeability and impairing energy metabolism induced by oxidative burst. Practical applications: One of the most economically important postharvest diseases of citrus fruit is green mold caused by Penicillium digitatum. The pathogen is mainly controlled by using imazalil, but the prolonged and extensive application of this chemical fungicide has led to emergence of numerous IMZ‐resistant strains among P. digitatum isolates. Consequently, new and safe strategies for controlling citrus green mold caused by IMZ‐resistant P. digitatum strains are urgently needed. In this study, an alkaloid antofine effectively inhibited the growth of IMZ‐resistant P. digitatum strain Pdw03 and significantly decreased green mold incidence in the affected citrus fruits. Antofine induced membrane lipid peroxidation of Pdw03 mycelia, resulting in damage to the cell membrane and impairment of energy metabolism. Antofine is therefore a potential antifungal agent for the control of green mold, which provide theoretical guidance for the food industry. [ABSTRACT FROM AUTHOR]

• This review briefly introduces the contributor role of ferroptosis in stroke. • Ferroptosis inhibitors exhibit neuroprotective effects in multiple stroke models. • The potential of ferroptosis inhibitors in stroke therapeutics is discussed. Stroke ranks as the second leading cause of death across the globe. Despite advances in stroke therapeutics, no US Food and Drug Administration (FDA)-approved drugs that can minimize neuronal injury and restore neurological function are clinically available. Ferroptosis, a regulated iron-dependent form of nonapoptotic cell death, has been shown to contribute to stroke-mediated neuronal damage. Inhibitors of ferroptosis have also been validated in several stroke models of ischemia or intracerebral hemorrhage. Herein, we review the therapeutic activity of inhibitors of ferroptosis in stroke models. We further summarize previously reported neuroprotectants that show protective effects in stroke models that have been recently validated as ferroptosis inhibitors. These findings reveal new mechanisms for neuroprotection and highlight the importance of ferroptosis during stroke processes. Ferroptosis inhibitors are promising neuroprotectants in stroke therapy. [ABSTRACT FROM AUTHOR]

The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway serves as a crucial regulator against oxidative stress (OS) damage in various cells and organs. It has garnered significant attention as a potential therapeutic target for neurodegenerative diseases (NDD). Although progress has been achieved in strategies to regulate the Keap1–Nrf2 pathway, the availability of Nrf2 activators applicable to NDD is currently limited. Currently, the FDA has approved the Nrf2 activators dimethyl fumarate (DMF) and Omaveloxolone (Omav) as novel first-line oral drugs for the treatment of patients with relapsing forms of multiple sclerosis and Friedreich's ataxia. A promising alternative approach involves the direct inhibition of Keap1–Nrf2 protein-protein interactions (PPI), which offers numerous advantages over the use of electrophilic Nrf2 activators, primarily in avoiding off-target effects. This review examines the compelling evidence supporting the beneficial role of Nrf2 in NDD and explores the potential of Keap1 inhibitors and Keap1–Nrf2 PPI inhibitors as therapeutic agents, with the aim to provide further insights into the development of inhibitors targeting this pathway for the treatment of NDD. [Display omitted] • An overview of the structures and functions of small molecule inhibitors of Keap1–Nrf2 axis. • Elucidate the mechanism of action of Keap1–Nrf2 axis. • A review of recently reported Keap1 inhibitors and Keap1–Nrf2 PPI inhibitors, as well as their mechanisms of action and structure-activity relationships. • Summarize the future directions and application prospects of small molecule inhibitors of Keap1–Nrf2 axis for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel scaffold and potent PARP1 PROTAC D6 was discovered by introduction of nitrogen heterocyclic linkers. • D6 exhibited remarkable selectivity of PARP1 degradation and demonstrated moderate oral absorption property. • The antitumor mechanism of D6 was elucidated by intercepting the CDC25C-CDK1 axis, thereby arresting cell cycle progression. PARP1 is a multifaceted component of DNA repair and chromatin remodeling, making it an effective therapeutic target for cancer therapy. The recently reported proteolytic targeting chimera (PROTAC) could effectively degrade PARP1 through the ubiquitin–proteasome pathway, expanding the therapeutic application of PARP1 blocking. In this study, a series of nitrogen heterocyclic PROTACs were designed and synthesized through ternary complex simulation analysis based on our previous work. Our efforts have resulted in a potent PARP1 degrader D6 (DC 50 = 25.23 nM) with high selectivity due to nitrogen heterocyclic linker generating multiple interactions with the PARP1-CRBN PPI surface, specifically. Moreover, D6 exhibited strong cytotoxicity to triple negative breast cancer cell line MDA-MB-231 (IC 50 = 1.04 µM). And the proteomic results showed that the antitumor mechanism of D6 was found that intensifies DNA damage by intercepting the CDC25C-CDK1 axis to halt cell cycle transition in triple-negative breast cancer cells. Furthermore, in vivo study, D6 showed a promising PK property with moderate oral absorption activity. And D6 could effectively inhibit tumor growth (TGI rate = 71.4 % at 40 mg/kg) without other signs of toxicity in MDA-MB-321 tumor-bearing mice. In summary, we have identified an original scaffold and potent PARP1 PROTAC that provided a novel intervention strategy for the treatment of triple-negative breast cancer. [ABSTRACT FROM AUTHOR]

Inadequate cytoreductive surgery (CRS) has been identified as a prognostic factor for poor patient outcomes in cases of peritoneal metastasis. While imaging probes are used to identify peritoneal metastasis to facilitate CRS, many of these probes exhibit high background signals, resulting in a significant delay in achieving a satisfactory tumor-to-normal ratio (TNR) due to prolonged clearance time. In this study, we designed a novel fluorescent probe named Tras-AA-Cy NH 2 , which enables the relatively rapid imaging of subcutaneous tumors and peritoneal tumors while maintaining a high TNR. Mechanistically, Tras-AA-Cy NH 2 exhibits selective targeting towards the Human epidermal growth factor receptor 2 on the surface of cancer cells. Following internalization, it undergoes enzymatic cleavage catalyzed by the overexpressed cathepsin, leading to the subsequent release of near-infrared fluorophores. Consequently, Tras-AA-Cy NH 2 achieved a TNR of 7.8 at 6 h and 21.4 at 24 h in subcutaneous tumor mice. Even after 522 h of in vivo circulation, the TNR remained above 5, indicating an ultralong imaging time window. It is noteworthy that Tras-AA-Cy NH 2 has demonstrated successful utilization for peritoneal tumor-specific imaging and further affirmed its tumor tissue-specific recognition capability using human resected tissues. In summary, these findings underscore the rational design of Tras-AA-Cy NH 2 for visualizing peritoneal tumors. [Display omitted] • Tras-AA-Cy NH 2 achieved a TNR of 21.4 at 24 h in subcutaneous tumor mice. • Tras-AA-Cy NH 2 enables specific imaging of mice peritoneal tumors and human ex vivo tumor tissues. • Tras-AA-Cy NH 2 offers a potential approach to extending the time window (6–522 h) for surgery. [ABSTRACT FROM AUTHOR]

BRD9 is essential in regulating gene transcription and chromatin remodeling, and blocking BRD9 profoundly affects the survival of AML cells. However, the inhibitors of BRD9 suffer from various drawbacks, including poor phenotype and selectivity, and BRD9 PROTACs still face the challenge of druggability, which limits the development of blocking BRD9 in AML. This study described an oral activity BRD9 PROTAC C6 by recruiting the highly efficient E3 ligase. C6 demonstrated remarkable efficacy and selectivity in BRD9 degradation with a BRD9 degradation DC 50 value of 1.02 ± 0.52 nM and no degradation of BRD4 or BRD7. Moreover, our findings highlighted its therapeutic potential, as evidenced by profound in vitro activity against the AML cell line MV4-11. Furthermore, C6 exhibited superior oral activity, with a C max value of 3436.95 ng/mL. These findings demonstrated that C6 , as a novel BRD9 PROTAC with remarkable pharmacodynamic and pharmacokinetic properties, had the potential to be developed as a promising therapeutic agent for AML treatment. [Display omitted] • A new PROTAC C6 with potent and selective BRD9 degradation activity was identified. • Compound C6 showed potent MV4-11 inhibition activity based on rational design. • C6 exhibited significantly oral activity in ICR mice with the Cmax value of 3436.95 ng/mL. [ABSTRACT FROM AUTHOR]

Ticagrelor is the first reversible P2Y12 receptor antagonist that inhibits ADP‐induced platelet aggregation. In several areas of biomedical research, the deuterium strategy has been employed to slow down the rate of drug metabolism and improve the pharmacokinetic properties of drugs. In the present study, several deuterated analogs of ticagrelor, as well as their prodrugs, were designed and synthesized in order to improve the metabolic stability of ticagrelor. Further in vitro and in vivo pharmacokinetic experiments using the deuterated derivates 24 and 25 demonstrated that the metabolic stability of deuterated compounds was improved compared to that of the parent compound. In addition, the half‐life of the deuterated valine ester prodrug 31 (t1/2 =2.54±0.32 h) was significantly lengthened, reaching a value of approximately 40 % longer than that of ticagrelor (t1/2=1.77±0.14 h). [ABSTRACT FROM AUTHOR]

Background: Alternaria sp. MG1, an endophytic fungus isolated from grape, is a native producer of resveratrol, which has important application potential. However, the metabolic characteristics and physiological behavior of MG1 still remains mostly unraveled. In addition, the resveratrol production of the strain is low. Thus, the whole-genome sequencing is highly required for elucidating the resveratrol biosynthesis pathway. Furthermore, the metabolic network model of MG1 was constructed to provide a computational guided approach for improving the yield of resveratrol. Results: Firstly, a draft genomic sequence of MG1 was generated with a size of 34.7 Mbp and a GC content of 50.96%. Genome annotation indicated that MG1 possessed complete biosynthesis pathways for stilbenoids, flavonoids, and lignins. Eight secondary metabolites involved in these pathways were detected by GC–MS analysis, confirming the metabolic diversity of MG1. Furthermore, the first genome-scale metabolic network of Alternaria sp. MG1 (named iYL1539) was reconstructed, accounting for 1539 genes, 2231 metabolites, and 2255 reactions. The model was validated qualitatively and quantitatively by comparing the in silico simulation with experimental data, and the results showed a high consistency. In iYL1539, 56 genes were identified as growth essential in rich medium. According to constraint-based analysis, the importance of cofactors for the resveratrol biosynthesis was successfully demonstrated. Ethanol addition was predicted in silico to be an effective method to improve resveratrol production by strengthening acetyl-CoA synthesis and pentose phosphate pathway, and was verified experimentally with a 26.31% increase of resveratrol. Finally, 6 genes were identified as potential targets for resveratrol over-production by the recently developed methodology. The target-genes were validated using salicylic acid as elicitor, leading to an increase of resveratrol yield by 33.32% and the expression of gene 4CL and CHS by 1.8- and 1.6-fold, respectively. Conclusions: This study details the diverse capability and key genes of Alternaria sp. MG1 to produce multiple secondary metabolites. The first model of the species Alternaria was constructed, providing an overall understanding of the physiological behavior and metabolic characteristics of MG1. The model is a highly useful tool for enhancing productivity by rational design of the metabolic pathway for resveratrol and other secondary metabolites. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The integration of docking scores, key interaction profiles remarkably improved the accuracy of the QSAR models. • The established MD-SVR (Molecular Docking Based SVM regression) model was applied on designing new NIK inhibitors. • The identified compounds would be promising leads for finding highly potent NIK inhibitors. Abstract A set of NF-κB-inducing kinase (NIK) inhibitors was used to develop a molecular docking-based QSAR model by using nonlinear regression method. The accuracy of the QSAR model was remarkably improved by integrating the docking scores and key interaction profiles. Two indole-aminopyrimidine derivatives 32a and 32b predicted as NIK inhibitors were synthesized and biologically evaluated. The significant correlationship between experimental data and MD-SVR model-predicted results were observed. The binding mode of 32a and 32b with NIK were further investigated by dynamic simulations. Compound 32b was proposed as a promising lead for the findings of highly potent inhibitors. [ABSTRACT FROM AUTHOR]

BACKGROUND Phomopsis sp. XP-8 is an endophytic fungus with the ability to produce pinoresinol diglucoside ( PDG) in vitro and thus has potential application in biosynthesis of PDG independent of plants. In order to enhance the production of PDG, 18 different natural materials were tested in solid-state cultivation of Phomopsis sp. XP-8. RESULTS Most of the tested natural materials promoted the production of PDG. A supplement derived from mung beans produced the highest PDG yield and better fungal growth than the other materials. Also, pinoresinol monoglucoside, pinoresinol and other substrates (phenylalanine, p-coumaric acid, cinnamic acid, caffeic acid, and ferulic acid) were obtained after fermentation on mung beans. Furthermore, PDG production was much higher when mung beans were incorporated into solid state agar versus a liquid medium. The highest pinoresinol diglucoside production (72.1 mg kg−1 in fresh culture) was obtained in 9 days using a solid state culture of Phomopsis sp. XP-8 on a mung bean grain medium containing 100 g kg−1 glucose. Mung bean water-soluble polysaccharide was identified as a major promoter of PDG production by Phomopsis sp. XP-8. CONCLUSION Mung bean, especially its water-soluble polysaccharide fraction, was an efficient natural material to promote PDG production by Phomopsis sp. XP-8. © 2015 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

The Hippo pathway is an evolutionarily conserved signaling pathway that plays critical roles in the tumorigenesis and progression of breast cancer, oral cancer, rectal cancer, colloid cancer, and so on. YAP/TAZ-TEAD complex is a key knot in the Hippo pathway regulating cell proliferation and stem cell functions. Activation or overexpression of this complex has been proved to lead to cell transformation, proliferation and eventually cancerization. In this review, the association between the alterations of hippo pathway and tumorigenesis of various cancer had been elucidated. The structural basis of YAP/TAZ-TEAD complex is analyzed, and the targeting inhibitors are summarized within the medicinal chemistry classification. Moreover, we have also discussed the clinical status and current challenges of these drug candidates, and provide guidance for the future development of inhibitors targeting this pathway, especially YAP/TAZ-TEAD complex. [Display omitted] • The roles of the hippo pathway played in the tumorigenesis were elucidated. • The crystal structure of the YAP/TAZ-TEAD complexes were analyzed. • The small molecules targeting YAP/TAZ and TEAD were summarized. • Providing guidance for the discovery of novel effective TEAD inhibitors. [ABSTRACT FROM AUTHOR]

Targeted activatable fluorescent probes could provide an effective approach for colorectal cancer imaging. In this study, F1 was found as an effective targeted activatable fluorescent probe based on log P analysis. In vitro experiments demonstrated that the initial fluorescence of the developed probe F1 was initially well quenched, and the fluorescence increased after the probe interacted with glutathione. Cell imaging results showed that the probe had good cell permeability and selectivity. Remarkably, F1 displayed enhanced tumor tissue fluorescence in MC-38 tumor-bearing mice. Notably, it showed selectivity in imaging clinical specimens of human colorectal cancer tissues. Accordingly, this study shows that log P analysis can facilitate the developing efficient of biotin-tagged activatable probes, and the identified F1 has a good potential in clinical colorectal cancer diagnosis. [Display omitted] • The fluorescence signal after F1 activation can be enhanced 67-fold. • F1 was found as an effective targeted activatable fluorescent probe. • F1 showed selectivity in imaging the clinical specimens of human CRC tissues. • The potential utility of log P analysis in biotin-tagged activatable probes design. [ABSTRACT FROM AUTHOR]

AKT and associated signaling pathways have been recognized as promising therapeutic targets for decades, and growing evidence indicates that inhibition or degradation of cellular AKT are viable strategies to treat cancer. Guided by an in silico modeling approach for rational linker design and based on our previous work in this field, we herein efficiently synthesized a small group of cereblon-recruiting AKT PROTAC molecules and identified a highly potent AKT degrader B4. Compared to the existing AKT degraders, B4 has a structurally unique AKT targeting warhead derived from the pyrazole-furan conjugated piperidine derivatives. It induces selective degradation of all three isoforms of AKT and exhibits efficacious anti-proliferation against several human hematological cancers. Notably, B4 demonstrates potent inhibition of AKT downstream signaling superior to its parental inhibitor. Together with its active analogs, B4 expands the arsenal of AKT chemical degraders as a valuable probe to uncover AKTs new functions and as a potential drug candidate to treat cancer. [Display omitted] • Structure-based rational linker design enables efficient discovery of AKT degrader B4. • B4 rapidly depletes cellular AKT and strongly suppresses AKT downstream signaling. • B4 potently inhibits MCL and MM cell growth and synergizes with Ibrutinib in cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of dihydropyridine-based PD-L1 degraders were designed and synthesized. • Summarize the SAR of dihydropyridine derivatives for the degradation of PD-L1. • Compounds maintain PD-L1 degradation after attenuating calcium channel blockade. • F4 showed best degradation activity (66.99% @20 μM) but no calcium blocking effect. • F4- induced PD-L1 degradation strengthen the T cell-mediated killing of tumor cells. Immune checkpoint blockade (ICB) by targeting programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway is a promising strategy for tumor immunotherapy. Developing small-molecules inducing PD-L1 protein degradation has been proven as an alternative and useful approach for targeting the immunotherapy pathway. Our previous study showed that Lercanidipine could down-regulate the expression of PD-L1 protein, but its calcium influx antagonistic activity hampers further development. For attenuating the unexpected calcium channel blockade effect, a series of compounds were synthesized and evaluated through structure-activity relationship (SAR) exploration. Amongst, compound F4 exhibited a loss of calcium antagonistic activity, while the PD-L1 degradation activity can still retain. Further studies indicated that F4 degraded PD-L1 dose- and time-dependently, and may function through a lysosomal-dependent manner. Furthermore, compound F4 showed a good bioavailability value of 24.9% in mice. Moreover, the F4- induced PD-L1 degradation strengthened the T cell-mediated killing of tumor cells. Our findings show the discovery of a new PD-L1 degrader, providing a potential strategy for immunotherapy. [ABSTRACT FROM AUTHOR]

Pinoresinol diglucoside (PDG) and pinoresinol (Pin) are normally produced by plant cells via the phenylpropanoid pathway. This study reveals the existence of a related pathway in Phomopsis sp. XP-8, a PDG-producing fungal strain isolated from the bark of the Tu-chung tree (Eucommiaulmoides Oliv.). After addition of 0.15 g/L glucose to Phomopsis sp. XP-8, PDG and Pin formed when phenylalanine, tyrosine, leucine, cinnamic acid, and p-coumaric acid were used as the substrates respectively. No PDG formed in the absence of glucose, but Pin was detected after addition of all these substrates except leucine. In all systems in the presence of glucose, production of PDG and/or Pin and the accumulation of phenylalanine, cinnamic acid, or p-coumaric acid correlated directly with added substrate in a time- and substrate concentration- dependent manner. After analysis of products produced after addition of each substrate, the mass flow sequence for PDG and Pin biosynthesis was defined as: glucose to phenylalanine, phenylalanine to cinnamic acid, then to p-coumaric acid, and finally to Pin or PDG. During the bioconversion, the activities of four key enzymes in the phenylpropanoid pathway were also determined and correlated with accumulation of their corresponding products. PDG production by Phomopsis sp. exhibits greater efficiency and cost effectiveness than the currently-used plant-based system and will pave the way for large scale production of PDG and/or Pin for medical applications. [ABSTRACT FROM AUTHOR]

[Display omitted] • Homology modeling to construct high-quality CXCR1 protein structure. • Molecular docking and dynamics simulation reveal the binding mode of compounds to CXCR1/2. • CXCR1/2 selectivity lies in the difference of the key amino acids ASN311(CXCR1) and LYS320(CXCR2). CXC chemokine receptors 1 (CXCR1) and 2 (CXCR2) are the members of the GPCRs (G-protein coupled receptors) family, and have been demonstrated to play an important role in proliferation, apoptosis and angiogenesis of cancer cells. The high sequence homology between CXCR1 and CXCR2 makes it a great challenge to develop selective antagonists for CXCR1/2. To reveal the molecular mechanism of selective CXCR1/2 antagonism, a systematic computational method, including homology modeling, molecular docking, molecular dynamics simulation and free energy calculations, had been carried out. It turned out that the differences between the corresponding amino acids ASN311 on CXCR1 and LYS320 on CXCR2 is the main reason for the different antagonistic ability of CXCR1/2, which provide important hint for the development of CXCR1/2 selective antagonists. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a highly malignant hematologic cancer that occurs when an atypical plasma cell develops in the bone marrow and reproduces quickly. Despite varies of new drugs have been developed or under clinic trial, MM is still essentially incurable, while XPO1 inhibition has emerged as a promising therapeutic strategy in the treatment of MM. Using the second-generation XPO1 inhibitor KPT-8602 as the lead compound, structure-based optimization provided D4 with high anti-proliferation efficacy (IC 50 = 24 nM in MM.1S). In addition, the treatment with D4 significantly induced MM.1S cell cycle arrested and cell apoptosis, which was confirmed as on-target effect by immunofluorescence microscopy and competitive binding assay. Moreover, D4 displayed good metabolic stability over rat plasma and liver microsomes, as well as good pharmacokinetic profile on SD rat model with high drug exposure and decent bioavailability by oral gavage. All these good properties of D4 pave the way for further drug development and clinical application. [Display omitted] • The extensive SAR studies identify D4 as a promising XPO1 inhibitor. • D4 displayed lower IC 50 on multiple myeloma cell line than KPT8602. • D4 can efficiently induce cell apoptosis and cell cycle arrest. • D4 displayed favorable metabolic stability and PK profile. [ABSTRACT FROM AUTHOR]

Phomopsis sp. XP-8 is an endophytic fungus that has the ability to produce pinoresinol diglucoside (PDG) in vitro and thus has potential application for the biosynthesis of PDG independent of plants. When cultivated in mung bean medium, PDG production was significantly improved and pinoresinol monoglucoside (PMG) and pinoresinol (Pin) were also found in the culture medium. In this experiment, starch, protein, and polysaccharides were isolated from mung beans and separately used as the sole substrate in order to explore the mechanism of fermentation and identify the major substrates that attributed to the biotransformation of PDG, PMG, and Pin. The production of PDG, PMG, and Pin was monitored using high-performance liquid chromatography (HPLC) and confirmed using HPLC-MS. Activities of related enzymes, including phenylalanine ammonia-lyase (PAL), trans-cinnamate 4-hydroxylase (C4H), and 4-coumarate-CoA ligase (4CL) were analyzed and tracked during the cultivation. The reaction system contained the compounds isolated from mung bean in the designed amount. Accumulation of phenylalanine, cinnamic acid, p-coumaric acid, PDG, PMG, and Pin and the activities of PAL, C4H, and 4CL were measured during the bioconversion. PMG was found only when mung bean polysaccharide was analyzed, while production of PDG and Pin were found when both polysaccharide and starch were analyzed. After examining the monosaccharide composition of the mung bean polysaccharide and the effect of the different monosaccharides had on the production of PMG, PDG, and Pin, galactose in mung bean polysaccharide proved to be the major factor that stimulates the production of PMG. [ABSTRACT FROM AUTHOR]

Aberrant activation of the fibroblast growth factor 19-fibroblast growth factor receptor 4 (FGF19-FGFR4) signaling pathway has been proved to promote hepatocellular carcinoma (HCC) proliferation. It is assumed that the first FGFR4 inhibitor BLU9931 did not enter clinical studies, presumably due to its rapid metabolism in liver microsomes. Here, we report the development of series of quinazoline derivatives based on FGFR4 inhibitor BLU9931 through structural modification of its solvent region pocket to minimize its potential metabolic liability. Among them, compound 35a exhibited comparable or superior kinase inhibitory activity (IC50 = 8.5 nM) and selectivity in cells. More importantly, compound 35a improved liver microsomes stability compared to BLU9931. Cellular mechanistic studies demonstrated that 35a induced apoptosis via the FGFR4 signaling pathway blockage. In addition, the computational simulation revealed the possible binding mode to FGFR4 protein, which provides a plausible explanation of high potent and metabolic stability. [Display omitted] • A series of quinazoline derivatives designed to minimize potential metabolism. • 35a displayed good FGFR4 inhibitory activity (IC 50 = 8.5 nM) and selectivity. • 35a improved liver microsomes stability compared to BLU9931. • 35a performed strong binding to FGFR4 by docking and dynamic simulation. [ABSTRACT FROM AUTHOR]

Programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) is one of the most promising targets in the field of immune checkpoint blockade therapy. Beginning with our exploration of linkers and structure-activity relationship research, we found that the aromatic ring could replace the linker and aryl group to maintain the satisfactory activity of classic triaryl scaffold inhibitor. Based on previous studies, we designed and synthesized a series of C 2 -symmetric phenyl-linked compounds, and further tail optimization afforded the inhibitors, which displayed promising inhibitory activity against the PD-1/PD-L1 interaction with IC 50 value at the single nanomolar range (C13–C15). Further cell-based PD-1/PD-L1 blockade bioassays indicated that these C 2 -symmetric molecules could significantly inhibit the PD-1/PD-L1 interaction at the cellular level and restore T cells' immune function at the safety concentrations. The discovery of these phenyl-linked symmetric small molecules showed the potential of simplified-linker and C 2 -symmetric strategy and provided a basis for developing symmetric small molecule inhibitors of PD-1/PD-L1 interaction. Moreover, C13 and C15 performed stable binding modes to PD-L1 dimeric after computational docking and dynamic simulation, which may serve as a good starting point for further development. [Display omitted] • A series of phenyl-linked symmetric compounds were synthesized and evaluated. • In cell-based PD-L1 blockade assay, C13–C15 showed promising RLU max and EC 50. • C13 and C15 significantly induced IFN-γ production at the safety concentrations. • Compound C13 and C15 performed stable binding mode to PD-L1 dimeric. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is one of the most common pediatric malignancies. Easy metastasis, poor prognosis, and a high degree of heterogeneity of NB hinder its successful treatment. Several different therapeutic strategies have been developed to overcome these problems, including differentiation and targeted therapy. In this review, we summarize the recent development of differentiation modulators and targeted agents for treating NB. Several promising targets of NB were also discussed. Image 1 • The current status of clinical diagnosis and therapy for neuroblastoma was intruoduced. • The existing differentiation modulators and targeted agents for treating neuroblastoma were summarized. • The new targets related to NB differentiation were discussed. [ABSTRACT FROM AUTHOR]

• Antofine was isolated and identified from Cynanchum atratum. • Antofine treatment significantly reduced the green mold in citrus fruit. • Antofine destroyed the membrane integrity and permeability of Penicillium digitatum. • Antofine did not impair the cell wall integrity of P. digitatum. • Antofine caused a disruption in the energy metabolism. The present study describes the isolation of the alkaloid "antofine" from Cynanchum atratum BUNGE as well as its anti-fungal potential against the citrus postharvest pathogen Penicillium digitatum. Antofine, which was extracted using an ultrasonic-assisted method and identified by 1H, 13C-NMR, and LC/MS analysis, showed strong antifungal activity against P. digitatum , with an observed minimum inhibitory concentration (MIC) and a minimum fungicidal concentration (MFC) of 1.56 × 10−3 and 1.25 × 10-2 g L-1, respectively. In vivo assays showed that antofine could significantly reduce the incidence of green mold. Furthermore, the total lipid and ergosterol contents of P. digitatum decreased after antofine treatment, indicating the disruption of membrane integrity. In addition, antofine caused a significant reduction of the intracellular adenosine triphosphate (ATP) content during the entire exposure period. These results suggest that the antifungal activity of antofine against P. digitatum can be attributed to the disruption of the cell membrane integrity and energy metabolism. [ABSTRACT FROM AUTHOR]