Discovery of reversible and covalent TEAD 1 selective inhibitors MSC-1254 and MSC-5046 based on one scaffold

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-05 DOI:10.1016/j.bmcl.2024.129981

Emma Carswell , Timo Heinrich , Carl Petersson , Jakub Gunera , Sakshi Garg , Daniel Schwarz , Sarah Schlesiger , Frank Fischer , Thomas Eichhorn , Mathew Calder , Geoffrey Smith , Ellen MacDonald , Hollie Wilson , Katherine Hazel , Elisabeth Trivier , Rebecca Broome , Alexander Balsiger , Sameer Sirohi , Djordje Musil , Filipe Freire , Dirk Wienke

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Abstract

The Transcriptional Enhanced Associated Domain (TEAD) family of transcription factors are key components of the Hippo signalling family which play a crucial role in the regulation of cell proliferation, differentiation and apoptosis. The identification of inhibitors of the TEAD transcription factors are an attractive strategy for the development of novel anticancer therapies. A HTS campaign identified hit 1, which was optimised using structure-based drug design, to deliver potent TEAD1 selective inhibitors with both a reversible and covalent mode of inhibition. The preference for TEAD1 could be rationalised by steric differences observed in the lower pocket of the palmitoylation-site between subtypes, with TEAD1 having the largest available volume to accommodate substitution in this region.

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基于一个支架发现可逆的共价 TEAD 1 选择性抑制剂 MSC-1254 和 MSC-5046。

转录增强相关域（TEAD）转录因子家族是希波信号家族的关键组成部分，在细胞增殖、分化和凋亡的调控中发挥着至关重要的作用。确定 TEAD 转录因子的抑制剂是开发新型抗癌疗法的一个有吸引力的策略。一项 HTS 研究发现了 1 号靶点，并利用基于结构的药物设计对其进行了优化，以提供具有可逆和共价抑制模式的强效 TEAD1 选择性抑制剂。在不同亚型的棕榈酰化位点下部口袋中观察到的立体结构差异可合理解释对 TEAD1 的偏好，TEAD1 在该区域具有最大的可用容积来容纳取代。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.