Di Fruscia Paolo, Edfeldt Fredrik, Shamovsky Igor, Collie Gavin W, Aagaard Anna, Barlind Louise, Börjesson Ulf, Hansson Eva L, Lewis Richard J, Nilsson Magnus K, Öster Linda, Pemberton Josefine, Ripa Lena, Storer R Ian, Käck Helena
Structure Biophysics & Fragments, Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom.
Structure Biophysics & Fragments, Discovery Sciences, R&D, AstraZeneca, Gothenburg 431 83, Sweden.
ACS Med Chem Lett. 2021 Jan 27;12(2):302-308. doi: 10.1021/acsmedchemlett.0c00563. eCollection 2021 Feb 11.
The MEK1 kinase plays a critical role in key cellular processes, and as such, its dysfunction is strongly linked to several human diseases, particularly cancer. MEK1 has consequently received considerable attention as a drug target, and a significant number of small-molecule inhibitors of this kinase have been reported. The majority of these inhibitors target an allosteric pocket proximal to the ATP binding site which has proven to be highly druggable, with four allosteric MEK1 inhibitors approved to date. Despite the significant attention that the MEK1 allosteric site has received, chemotypes which have been shown structurally to bind to this site are limited. With the aim of discovering novel allosteric MEK1 inhibitors using a fragment-based approach, we report here a screening method which resulted in the discovery of multiple allosteric MEK1 binders, one series of which was optimized to sub-μM affinity for MEK1 with promising physicochemical and ADMET properties.
MEK1激酶在关键细胞过程中发挥着关键作用，因此，其功能障碍与多种人类疾病，尤其是癌症密切相关。因此，MEK1作为药物靶点受到了广泛关注，并且已经报道了大量该激酶的小分子抑制剂。这些抑制剂中的大多数靶向ATP结合位点附近的变构口袋，该口袋已被证明具有高度可成药性，迄今为止已有四种变构MEK1抑制剂获批。尽管MEK1变构位点受到了广泛关注，但在结构上已显示与该位点结合的化学类型却很有限。为了使用基于片段的方法发现新型变构MEK1抑制剂，我们在此报告一种筛选方法，该方法导致发现了多种变构MEK1结合剂，其中一系列结合剂被优化至对MEK1具有亚微摩尔亲和力，并具有良好的物理化学性质和药物代谢及毒性性质。
