基于非手性小脑E3连接酶配体的部分蛋白水解靶向嵌合体文库的建立及其在布鲁顿酪氨酸激酶降解物中的应用

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-09-17 DOI:10.1002/cmdc.202500209
Chelsi M Almodóvar-Rivera, Ira Tandon, Ramesh Mudududdla, Paulina N Esguerra, Kevin Lucio-Acero, Weiping Tang
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引用次数: 0

摘要

蛋白水解靶向嵌合体(PROTACs)通过利用泛素-蛋白酶体系统(UPS)降解靶蛋白提供了一种很有前途的治疗方法。这些异双功能分子由靶蛋白配体、E3连接酶配体和连接体组成。在有限的E3连接酶配体中,小脑(CRBN)配体是应用最广泛的配体。然而,目前手性CRBN配体的稳定性和外消旋化给开发CRBN招募PROTAC疗法带来了挑战。本文报道了部分PROTAC文库将醛基序和各种连接物结合到先前开发的非手性苯基二氢脲嘧啶CRBN配体中,从而提高了稳定性并消除了外消旋化问题。通过将醛基序与含肼的BTK配体偶联,该库能够快速生成针对布鲁顿酪氨酸激酶(BTK)的全功能PROTACs。初始HiBiT试验(Promega)筛选确定了9个能够显著降解BTK的位点,其中化合物B1是最有效的降解物。一种稳定的酰胺生物同质体AM-B1被进一步开发,具有显著的抗增殖和BTK降解作用。机理研究证实BTK通过UPS降解。本研究重点开发了一个基于非手性crbn的部分PROTAC库,并展示了一个针对BTK的快速PROTAC开发的两阶段策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Development of a Partial Proteolysis Targeting Chimera Library Based on Achiral Cereblon E3 Ligase Ligands and its Application for Bruton's Tyrosine Kinase Degraders.

Proteolysis targeting chimeras (PROTACs) offer a promising therapeutic approach by leveraging the ubiquitin-proteasome system (UPS) to degrade target proteins. These heterobifunctional molecules consist of a target protein ligand, an E3 ligase ligand, and a linker. Among the limited E3 ligase ligands available, cereblon (CRBN) ligands are the most widely used. However, the stability and racemization of current chiral CRBN ligands pose challenges for developing CRBN-recruiting PROTAC therapeutics. Herein, a partial PROTAC library is reported incorporating an aldehyde motif and various linkers into previously developed achiral phenyl dihydrouracil CRBN ligands, which offer improved stability and eliminate racemization issues. This library enables the rapid generation of fully functional PROTACs targeting Bruton's tyrosine kinase (BTK) by coupling the aldehyde motif with a hydrazide-containing BTK ligand. Initial HiBiT assay (Promega) screening identifies nine hits capable of significant BTK degradation, with compound B1 emerging as the most potent degrader. A stable amide bioisostere, AM-B1, is further developed, which induces significant antiproliferation and BTK degradation. Mechanistic studies confirm BTK degradation via the UPS. This study highlights the development of an achiral CRBN-based partial PROTAC library and demonstrates a two-stage strategy for rapid PROTAC development against BTK.

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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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