Cancer Research Horizons, Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, UK.
Merck Healthcare KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
Bioorg Med Chem Lett. 2024 Dec 1;114:129981. doi: 10.1016/j.bmcl.2024.129981. Epub 2024 Oct 5.
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.
转录增强相关结构域（TEAD）转录因子家族是 Hippo 信号家族的关键组成部分，在调节细胞增殖、分化和凋亡方面发挥着重要作用。鉴定 TEAD 转录因子的抑制剂是开发新型抗癌疗法的一种有吸引力的策略。一项高通量筛选（HTS）活动鉴定到了化合物 1，该化合物通过基于结构的药物设计进行了优化，以提供具有可逆和共价抑制模式的强效 TEAD1 选择性抑制剂。在亚型之间的棕榈酰化位点的下口袋中观察到的立体差异可以合理地解释对 TEAD1 的偏好，TEAD1 具有最大的可用体积来容纳该区域的取代。
