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Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme with diverse biological functions in DNA synthesis. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate‐limiting enzyme involved in NAD+ biosynthesis in mammals. We developed the first chemical tool for optical control of NAMPT and NAD+ in biological systems using photoswitchable proteolysis‐targeting chimeras (PS‐PROTACs). An NAMPT activator and dimethylpyrazolazobenzene photoswitch were used to design highly efficient PS‐PROTACs, enabling up‐ and down‐reversible regulation of NAMPT and NAD+ in a light‐dependent manner and reducing the toxicity associated with inhibitor‐based PS‐PROTACs. PS‐PROTAC was activated under 620 nm irradiation, realizing in vivo optical manipulation of antitumor activity, NAMPT, and NAD+. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme with diverse biological functions in DNA synthesis. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate‐limiting enzyme involved in NAD+ biosynthesis in mammals. We developed the first chemical tool for optical control of NAMPT and NAD+ in biological systems using photoswitchable proteolysis‐targeting chimeras (PS‐PROTACs). An NAMPT activator and dimethylpyrazolazobenzene photoswitch were used to design highly efficient PS‐PROTACs, enabling up‐ and down‐reversible regulation of NAMPT and NAD+ in a light‐dependent manner and reducing the toxicity associated with inhibitor‐based PS‐PROTACs. PS‐PROTAC was activated under 620 nm irradiation, realizing in vivo optical manipulation of antitumor activity, NAMPT, and NAD+. [ABSTRACT FROM AUTHOR]

Many of the highest priority targets in a wide range of disease states are difficult‐to‐drug proteins. The development of reversible small molecule inhibitors for the active sites of these proteins with sufficient affinity and residence time on‐target is an enormous challenge. This has engendered interest in strategies to increase the potency of a given protein inhibitor by routes other than further improvement in gross affinity. Amongst these, the development of catalytic protein inhibitors has garnered the most attention and investment, particularly with respect to protein degraders, which catalyze the destruction of the target protein. This article discusses the genesis of the burgeoning field of catalytic inhibitors, the current state of the art, and exciting future directions. [ABSTRACT FROM AUTHOR]

Proteolysis targeting chimera (PROTAC) is a state‐of‐the‐art technology for ablating undruggable targets. A PROTAC degrader achieves targeted protein degradation (TPD) through the simultaneous binding of a protein of interest (POI) and an E3 ligase to form a ternary complex. A nanofibril‐based PROTAC strategy to form a polynary (E3)m : PROTAC : (POI)n complex has not been reported in the TPD field up to this point. A recent innovation shows that a POI ligand and E3 ligase ligand don't have to be within a fused degrader molecule. Instead, they can be recruited to cellular proximity by a self‐assembly‐driving peptide and click chemistry. The resulting nanofibrils can recruit multiple POI and E3 ligase molecules to form a polynary complex as a degradation center. The so‐called Nano‐PROTAC provides a novel approach for TPD in cancer therapy. [ABSTRACT FROM AUTHOR]

Ferroptosis is a new form of regulated, non‐apoptotic cell death driven by iron‐dependent phospholipid peroxidation. Its therapeutic potential is however, greatly limited by the low efficiency of regulating cell ferroptosis in vivo. Herein, we report a PROTAC‐based protein degrader that depletes endogenous glutathione peroxidase 4 (GPX4) and induces cancer cell ferroptosis. We demonstrate that a rationally designed GPX4 degrader, dGPX4, can deplete tumor cell GPX4 via proteasomal protein degradation, showing a five‐fold enhancement of ferroptosis induction efficiency compared to that of GPX4 inhibition using ML162. Moreover, we show that the intracellular delivery of dGPX4 using biodegradable lipid nanoparticles (dGPX4@401‐TK‐12) induces cell‐selective ferroptosis by targeting cancer cell microenvironment. The in vivo administration of dGPX4@401‐TK‐12 effectively suppresses tumor growth without appreciable side effects. We anticipate the protein degradation strategy described herein could be easily expanded to other essential regulatory proteins of ferroptosis for developing targeted cancer therapeutics. [ABSTRACT FROM AUTHOR]

The tumor suppressor p53 is the most frequently mutated gene in human cancer and more than half of cancers contain p53 mutations. The development of novel and effective therapeutic strategies for p53 mutant cancer therapy is a big challenge and highly desirable. Ubiquitin‐specific protease 7 (USP7), also known as HAUSP, is a deubiquitinating enzyme and proposed to stabilize the oncogenic E3 ubiquitin ligase MDM2 that promotes the proteosomal degradation of p53. Herein, we report the design and characterization of U7D‐1 as the first selective USP7‐degrading Proteolysis Targeting Chimera (PROTAC). U7D‐1 showed selective and effective USP7 degradation, and maintained potent cell growth inhibition in p53 mutant cancer cells, with USP7 inhibitor showing no activity. These data clearly demonstrated the practicality and importance of PROTAC as a preliminary chemical tool for investigating USP7 protein functions and a promising method for potential p53 mutant cancer therapy. [ABSTRACT FROM AUTHOR]

Lysine acylation plays pivotal roles in cell physiology, including DNA transcription and repair, signal transduction, immune defense, metabolism, and many other key cellular processes. Molecular mechanisms of dysregulated lysine acylation are closely involved in the pathophysiological progress of many human diseases, most notably cancers. In recent years, chemical biology tools have become instrumental in studying the function of post‐translational modifications (PTMs), identifying new "writers", "erasers" and "readers", and in targeted therapies. Here, we describe key developments in chemical biology approaches that have advanced the study of lysine acylation and its regulatory proteins (2016–2021). We further discuss the discovery of ligands (inhibitors and PROTACs) that are capable of targeting regulators of lysine acylation. Next, we discuss some current challenges of these chemical biology probes and suggest how chemists and biologists can utilize chemical probes with more discriminating capacity. Finally, we suggest some critical considerations in future studies of PTMs from our perspective. [ABSTRACT FROM AUTHOR]

Eine konservierte intrazelluläre allosterische Bindungsstelle (IABS) wurde kürzlich an mehreren G‐Protein‐gekoppelten Rezeptoren (GPCRs) identifiziert. Ausgehend von Vercirnon, einem intrazellulären Antagonisten am C−C‐Chemokin‐Rezeptor‐Typ‐9 (CCR9), entwickelten wir molekulare Werkzeuge, die an der IABS von CCR9 angreifen. Zunächst synthetisierten wir fluoreszierende CCR9‐Liganden, die Bindungsstudien via NanoBRET sowie Fluoreszenzmikroskopie ermöglichten. Deren Anwendung in zellfreien sowie zellulären Testsystemen erlaubte die Identifizierung eines 4‐Aminopyrimidin‐Analogons als neuen intrazellulären CCR9‐Antagonisten mit verbesserter Affinität. Um den proteasomalen Abbau von CCR9 einzuleiten, entwickelten wir das erste PROTAC, das die IABS von GPCRs als Angriffsort nutzt. In einer Machbarkeitsstudie zeigen wir, dass unser CCR9‐PROTAC in der Lage ist, die CCR9‐Spiegel zu reduzieren, was einen konzeptionell neuartigen Ansatz zur Modulation der GPCR‐Aktivität darstellt. [ABSTRACT FROM AUTHOR]

Protease inhibitors can modulate intratumoral metabolic processes to reprogram the immunosuppressive tumor microenvironment (TME), which however suffer from the limited efficacy and off‐targeted side effects. We report smart nano‐proteolysis targeting chimeras (nano‐PROTACs) with phototherapeutic ablation and cancer‐specific protein degradation to reprogram the TME for photo‐metabolic cancer immunotherapy. This nano‐PROTAC has a semiconducting polymer backbone linked with a cyclooxygenase 1/2 (COX‐1/2)‐targeting PROTAC peptide (CPP) via a cathepsin B (CatB)‐cleavable segment. CPP can be activated by the tumor‐overexpressed CatB to induce the degradation of COX‐1/2 via the ubiquitin‐proteasome system. The persistent degradation of COX‐1/2 depletes their metabolite prostaglandin E2 which is responsible for activation of immune suppressor cells. Such a smart PROTAC strategy synergized with phototherapy specifically reprograms the immunosuppressive TME and reinvigorates antitumor immunity. [ABSTRACT FROM AUTHOR]

Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis‐targeting chimera (PROTAC) approaches, owing to favorable drug‐like properties of CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known to be inherently unstable, readily undergoing hydrolysis in body fluids. Here we show that IMiDs and IMiD‐based PROTACs rapidly hydrolyze in commonly utilized cell media, which significantly affects their cell efficacy. We designed novel CRBN binders, phenyl glutarimide (PG) analogues, and showed that they retained affinity for CRBN with high ligand efficiency (LE >0.48) and displayed improved chemical stability. Our efforts led to the discovery of PG PROTAC 4 c (SJ995973), a uniquely potent degrader of bromodomain and extra‐terminal (BET) proteins that inhibited the viability of human acute myeloid leukemia MV4‐11 cells at low picomolar concentrations (IC50=3 pM; BRD4 DC50=0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN‐directed PROTACs. [ABSTRACT FROM AUTHOR]

Development of proteolysis targeting chimeras (PROTACs) is emerging as a promising strategy for targeted protein degradation. However, the drug development using the heterobifunctional PROTAC molecules is generally limited by poor membrane permeability, low in vivo efficacy and indiscriminate distribution. Herein an aptamer‐PROTAC conjugation approach was developed as a novel strategy to improve the tumor‐specific targeting ability and in vivo antitumor potency of conventional PROTACs. As proof of concept, the first aptamer‐PROTAC conjugate (APC) was designed by conjugating a BET‐targeting PROTAC to the nucleic acid aptamer AS1411 (AS) via a cleavable linker. Compared with the unmodified BET PROTAC, the designed molecule (APR) showed improved tumor targeting ability in a MCF‐7 xenograft model, leading to enhanced in vivo BET degradation and antitumor potency and decreased toxicity. Thus, the APC strategy may pave the way for the design of tumor‐specific targeting PROTACs and have broad applications in the development of PROTAC‐based drugs. [ABSTRACT FROM AUTHOR]

Defects in the functions of RNA binding proteins (RBPs) are at the origin of many diseases; however, targeting RBPs with conventional drugs has proven difficult. PROTACs are a new class of drugs that mediate selective degradation of a target protein through a cell's ubiquitination machinery. PROTACs comprise a moiety that binds the selected protein, conjugated to a ligand of an E3 ligase. Herein, we introduce RNA‐PROTACs as a new concept in the targeting of RBPs. These chimeric structures employ small RNA mimics as targeting groups that dock the RNA‐binding site of the RBP, whereupon a conjugated E3‐recruiting peptide derived from the HIF‐1α protein directs the RBP for proteasomal degradation. We performed a proof‐of‐concept demonstration with the degradation of two RBPs—a stem cell factor LIN28 and a splicing factor RBFOX1—and showed their use in cancer cell lines. The RNA‐PROTAC approach opens the way to rapid, selective targeting of RBPs in a rational and general fashion. [ABSTRACT FROM AUTHOR]

Multi‐Target‐Wirkstoffe stellen in der modernen Tumortherapie einen vielversprechenden Ansatz dar. Basierend auf dem bekannten Synergismus zwischen Histon‐Deacetylase‐Inhibitoren (HDACi) und alkylierenden Zytostatika präsentieren wir in dieser Arbeit die Entwicklung von alkylierenden HDACi, welche aus einer Pharmakophor‐Verknüpfungsstrategie hervorgegangen sind. Für die Synthese haben wir ein Protokoll entwickelt, bei dem Hydroxamsäuren an Festphasenharze immobilisiert und als vielseitig anwendbare Bausteine für die Synthese von funktionalisierten HDACi verwendet wurden. Verbindung 3 n zeigt eine signifikant bessere Induktion der Apoptose, Caspase‐3/7‐Aktivierung und Erzeugung von DNA‐Schäden als die Summe der biologischen Aktivitäten der einzelnen Pharmakophore. Um die Vielseitigkeit unserer beladenen Harze zu demonstrieren, wurde dieses Konzept auf die Synthese eines HDAC‐PROTAC 4 übertragen. Western‐Blot‐Experimente bestätigten, dass PROTAC 4 den Abbau von HDACs effizient induziert. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the aggregation of mutant huntingtin (mHtt), and removal of toxic mHtt is expected to be an effective therapeutic approach. We designed two small hybrid molecules ( 1 and 2) by linking a ligand for ubiquitin ligase (cellular inhibitor of apoptosis protein 1; cIAP1) with probes for mHtt aggregates, anticipating that these compounds would recruit cIAP1 to mHtt and induce selective degradation by the ubiquitin-proteasome system. The synthesized compounds reduced mHtt levels in HD patient fibroblasts and appear to be promising candidates for the development of a treatment for HD. [ABSTRACT FROM AUTHOR]

Die heutigen, auf Inhibitoren basierenden Therapieansätze sind zwangsläufig eingeschränkt durch 1) die Notwendigkeit von hoher systemischer Exposition, um ausreichende In‐vivo‐Effekte zu gewährleisten, 2) mögliche Nebenwirkungen aufgrund von hohen In‐vivo‐Konzentrationen des Wirkstoffs und 3) die Notwendigkeit, an ein aktives Zentrum zu binden, und die damit einhergehende Einschränkung der zugänglichen Zielproteine. Ein alternativer Ansatz nutzt einen neuen, katalytischen Mechanismus, um die Funktion eines Proteins irreversibel zu hemmen: den induzierten Abbau des Proteins durch die Rekrutierung an die zelluläre Maschinerie zur Qualitätskontrolle. Frühere Proteinabbau‐Strategien hatten kein hohes therapeutisches Anwendungspotenzial, doch neue Studien zu niedermolekularen PROTACs (“Proteolysis Targeting Chimeras”) haben gezeigt, dass diese Technik den Abbau von mehreren verschiedenen Proteinklassen überaus effizient vermitteln kann. Zerstörerische Chimären: Der durch niedermolekulare Verbindungen vom Typ der PROTACs („Proteolysis Targeting Chimeras”) ausgelöste Proteinabbau kann eine Alternative zu derzeitigen Inhibitor‐basierten Therapiekonzepten bieten. Neueste Erkenntnisse zur Entwicklung dieser Wirkstoffe werden beschrieben, und die Möglichkeiten und Herausforderungen der neuen Strategie werden diskutiert. [ABSTRACT FROM AUTHOR]

Rücktitelbild: Aptamer-PROTAC Conjugates (APCs) for Tumor-Specific Targeting in Breast Cancer (Angew. Keywords: aptamers; BET; drug design; PROTAC; tumor-specific Targeting EN aptamers BET drug design PROTAC tumor-specific Targeting 23656 23656 1 10/13/21 20211018 NES 211018 B PROTAC b ist eine aufstrebende neue Technologie in der Arzneimittelforschung. In ihrem Forschungsartikel auf S. 23487 entwickeln Guoqiang Dong, Chunquan Sheng et al. das erste Aptamer-PROTAC-Konjugat (APC), das eine verbesserte Tumoransteuerung und verbesserten In-vivo-Proteinabbau zeigt, was zu einer erhöhten Antitumor-Wirkung bei geringerer Toxizität führt. [Extracted from the article]