Identification and Evaluation of Reversible Covalent Binders to Cys55 of Bfl-1 from a DNA-Encoded Chemical Library Screen

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-05-20 DOI:10.1021/acsmedchemlett.4c00113

Simon C. C. Lucas*, J. Henry Blackwell, Ulf Börjesson, David Hargreaves, Alexander G. Milbradt, Samiyah Ahmed, Mark J. Bostock, Carine Guerot, Andrea Gohlke, Olaf Kinzel, Michelle L. Lamb, Nidhal Selmi, Christopher J. Stubbs, Nancy Su, Qibin Su, Haiou Luo, Ting Xiong, Xiaoqian Zuo, Sana Bazzaz, Corey Bienstock, Paolo A. Centrella, Kyle E. Denton, Diana Gikunju, Marie-Aude Guié, John P. Guilinger, Christopher Hupp, Anthony D. Keefe, Takashi Satoh, Ying Zhang and Emma L. Rivers,

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Abstract

Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound 13 was successfully cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.

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从 DNA 编码化学文库筛选中鉴定和评估 Bfl-1 Cys55 的可逆共价结合剂

Bfl-1 在血液肿瘤和实体瘤中都有过表达，因此，Bfl-1 的抑制剂是非常理想的。针对 Bfl-1 的 DNA 编码化学文库（DEL）筛选发现了首个已知的 Bfl-1 可逆共价小分子配体。这种结合通过生物物理和生物化学技术进行了验证，确认了可逆共价作用机制，并指出是通过 Cys55 结合的。这是首次从 DEL 筛选中发现氰基丙烯酰胺可逆共价化合物，并凸显了通过 DEL 筛选发现共价药物的更多机会。通过对命中化合物进行系统的 SAR 探索，药效提高了 10 倍。药效更强的类似物化合物 13 成功在 Bfl-1 中结晶，揭示了其结合模式，并提供了与 Cys55 发生共价作用的进一步证据。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.