Understanding the complexity of p53 in a new era of tumor suppression

Cancer Cell, Год журнала: 2024, Номер 42(6), С. 946 - 967

Опубликована: Май 9, 2024

Язык: Английский

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Histone lysine acetyltransferase inhibitors: an emerging class of drugs for cancer therapy

Trends in Pharmacological Sciences, Год журнала: 2024, Номер 45(3), С. 243 - 254

Опубликована: Фев. 20, 2024

Lysine acetyltransferases (KATs) are a family of epigenetic enzymes involved in the regulation gene expression; they represent promising class emerging drug targets. The frequent molecular dysregulation these enzymes, as well their mechanistic links to biological functions that crucial cancer, have led exploration around development small-molecule inhibitors against KATs. Despite early challenges, recent advances potent and selective enzymatic bromodomain (BRD) KAT inhibitors. In this review we discuss discovery new application oncology therapeutics. Additionally, chemically induced proximity approaches presented, offering opportunities for unique target selectivity profiles tissue-specific targeting Emerging clinical data CREB binding protein (CREBBP)/EP300 BRD KAT6 catalytic indicate promise cancer

Язык: Английский

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Expanding the horizons of targeted protein degradation: A non-small molecule perspective

Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 14(6), С. 2402 - 2427

Опубликована: Янв. 21, 2024

Targeted protein degradation (TPD) represented by proteolysis targeting chimeras (PROTACs) marks a significant stride in drug discovery. A plethora of innovative technologies inspired PROTAC have not only revolutionized the landscape TPD but potential to unlock functionalities beyond degradation. Non-small-molecule-based approaches play an irreplaceable role this field. wide variety agents spanning broad chemical spectrum, including peptides, nucleic acids, antibodies, and even vaccines, which prove instrumental overcoming constraints conventional small molecule entities also provided rapidly renewing paradigms. Herein we summarize burgeoning non-small technological platforms PROTACs, three major trajectories, provide insights for design strategies based on novel

Язык: Английский

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Targeting Tau Protein with Proximity Inducing Modulators: A New Frontier to Combat Tauopathies

ACS Pharmacology & Translational Science, Год журнала: 2025, Номер 8(3), С. 654 - 672

Опубликована: Фев. 10, 2025

Dysregulation of correct protein tau homeostasis represents the seed for development several devastating central nervous system disorders, known as tauopathies, that affect millions people worldwide. Despite massive public and private support to research funding, these diseases still represent unmet medical needs. In fact, tau-targeting tools developed date have failed translate into clinic. Recently, taking advantage modes nature uses mediate flow information in cells, researchers a new class molecules, called proximity-inducing modulators, which exploit spatial proximity modulate function(s) redirect cellular processes. this perspective, after brief discussion about classic approaches, we will discuss different classes modulators so far highlight applications protein's function tau-induced toxicity.

Язык: Английский

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Post-Translational Modifications and Diabetes

Biomolecules, Год журнала: 2024, Номер 14(3), С. 310 - 310

Опубликована: Март 6, 2024

Diabetes and its associated complications have increasingly become major challenges for global healthcare. The current therapeutic strategies involve insulin replacement therapy type 1 diabetes (T1D) small-molecule drugs 2 (T2D). Despite these advances, the complex nature of necessitates innovative clinical interventions effective treatment complication prevention. Accumulative evidence suggests that protein post-translational modifications (PTMs), including glycosylation, phosphorylation, acetylation, SUMOylation, play important roles in pathological consequences. Therefore, investigation PTMs not only sheds light on mechanistic regulation but also opens new avenues targeted therapies. Here, we offer a comprehensive overview role several diabetes, focusing most recent advances understanding their functions regulatory mechanisms. Additionally, summarize pharmacological targeting advanced into trials diabetes. Current future perspectives are provided.

Язык: Английский

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Targeted Covalent Modification Strategies for Drugging the Undruggable Targets

Chemical Reviews, Год журнала: 2025, Номер unknown

Опубликована: Янв. 7, 2025

The term "undruggable" refers to proteins or other biological targets that have been historically challenging target with conventional drugs therapeutic strategies because of their structural, functional, dynamic properties. Drugging such undruggable is essential develop new therapies for diseases where current treatment options are limited nonexistent. Thus, investigating methods achieve drugging an important challenge in medicinal chemistry. Among the numerous methodologies drug discovery, covalent modification has emerged as a transformative strategy. attachment diverse functional molecules provides powerful platform creating highly potent and chemical tools well ability provide valuable information on structures dynamics targets. In this review, we summarize recent examples biomolecules development therapeutics overcome discovery challenges highlight how contribute toward particular, focus use chemistry drugs, identification, screening, artificial modulation post-translational modifications, cancer specific chemotherapies, nucleic acid-based therapeutics.

Язык: Английский

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The First‐in‐class Deubiquitinase‐targeting Chimera Stabilizes and Activates cGAS

Angewandte Chemie International Edition, Год журнала: 2024, Номер unknown

Опубликована: Авг. 16, 2024

Abstract Deubiquitinase‐targeting chimera (DUBTAC) is a promising technology for inducing targeted protein stabilization (TPS). Despite its therapeutic potential, very few proteins have been stabilized by DUBTACs to date. The limited applicability of this likely due the modest DUBTAC‐induced effect, and scarcity effective deubiquitinase ligands that can be harnessed DUBTAC development. Here, we report discovery MS7829 MS8588, first‐in‐class cGAS, key component cGAS‐STING pathway. While these are based on cGAS inhibitor, they effectively activated cGAS/STING/IRF3 signaling. To develop DUBTACs, optimized EN523, an OTUB1 covalent ligand, into improved MS5105. We validated MS5105 generating MS5105‐based CFTR DUBTAC, which was approximately 10‐fold more in stabilizing ΔF508‐CFTR mutant than previously reported EN523‐based DUBTAC. Overall, work advances TPS.

Язык: Английский

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TAC‐tics for Leveraging Proximity Biology in Drug Discovery

ChemBioChem, Год журнала: 2023, Номер 25(4)

Опубликована: Ноя. 28, 2023

Abstract Chemically induced proximity (CIP) refers to co‐opting naturally occurring biological pathways using synthetic molecules recruit neosubstrates that are not normally encountered or enhance the affinity of interactions. Leveraging biology through CIPs has become a rapidly evolving field and garnered considerable interest in basic research drug discovery. PROteolysis TArgeting Chimera (PROTAC) is well‐established CIP modality induces between target protein an E3 ubiquitin ligase, causing degradation via ubiquitin‐proteasome system. Inspired by PROTACs, several other modalities have emerged modulate both proteins RNA over recent years. In this review, we summarize critical advances opportunities field, focusing on degraders, degraders non‐degrader such as post‐translational modification (PTM) protein‐protein interaction (PPI) modulators. We envision these emerging proximity‐based will be valuable resources for therapeutic discovery future.

Язык: Английский

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Small Molecule-Induced Post-Translational Acetylation of Catalytic Lysine of Kinases in Mammalian Cells

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(34), С. 23978 - 23988

Опубликована: Авг. 20, 2024

Reversible lysine acetylation is an important post-translational modification (PTM). This process in cells typically carried out enzymatically by acetyltransferases and deacetylases. The catalytic the human kinome highly conserved ligandable. Small-molecule strategies that enable of on kinases a target-selective manner therefore provide tremendous potential kinase biology. Herein, we report first small molecule-induced chemical strategy capable global from mammalian cells. By surveying various lysine-acetylating agents installed promiscuous kinase-binding scaffold, Ac4 was identified shown to effectively acetylate >100 different protein live Jurkat/K562 In order demonstrate this reversible kinases, further developed six acetylating compounds basis VX-680 (a noncovalent inhibitor AURKA). Among them, Ac13/Ac14, while displaying excellent vitro potency sustained cellular activity against AURKA, showed robust its (K162) manner, leading irreversible inhibition endogenous activity. reversibility confirmed Ac14-treated recombinant AURKA protein, followed deacetylation with SIRT3 deacetylase). Finally, Ac13-induced demonstrated SIRT3-transfected HCT116 disclosing cell-active both our could useful tool biology drug discovery.

Язык: Английский

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p53 protein abundance is a therapeutic window across TP53 mutant cancers and is targetable with proximity inducing small molecules

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 27, 2024

Abstract TP53 mutant cancers are associated with approximately half of cancer deaths. The most common mechanism p53 inactivation involves missense mutations. Such mutations in result a robust upregulation the protein. Here, we demonstrate an induced proximity approach to selectively kill cells. This uses increased abundance protein cells concentrate toxic molecules these We first generalizable strategy using small molecule binds Y220C and concentrates PLK1 inhibitor harboring Together, data that provides therapeutic window for can be translated into cell death signal proximity-inducing molecules.

Язык: Английский

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