Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2022-08-17 , DOI: 10.1016/j.bmcl.2022.128948 Gavin W Collie 1 , Louise Barlind 2 , Sana Bazzaz 3 , Ulf Börjesson 2 , Ian L Dale 1 , Jeremy S Disch 3 , Sevan Habeshian 3 , Rachael Jetson 3 , Puneet Khurana 1 , Andrew Madin 1 , Iacovos N Michaelides 1 , Ling Peng 4 , Arjan Snijder 2 , Christopher J Stubbs 1
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The c-MET receptor tyrosine kinase has received considerable attention as a cancer drug target yet there remains a need for inhibitors which are selective for c-MET and able to target emerging drug-resistant mutants. We report here the discovery, by screening a DNA-encoded chemical library, of a highly selective c-MET inhibitor which was shown by X-ray crystallography to bind to the kinase in an unprecedented manner. These results represent a novel mode of inhibiting c-MET with a small molecule and may provide a route to targeting drug-resistant forms of the kinase whilst avoiding potential toxicity issues associated with broad kinome inhibition.
中文翻译：
发现具有新型结合模式的选择性 c-MET 抑制剂
c-MET 受体酪氨酸激酶作为癌症药物靶点已受到相当多的关注，但仍然需要对 c-MET 具有选择性并能够靶向新兴耐药突变体的抑制剂。我们在此报告通过筛选 DNA 编码的化学文库，发现了一种高度选择性的 c-MET 抑制剂，X 射线晶体学显示该抑制剂以前所未有的方式与激酶结合。这些结果代表了一种用小分子抑制 c-MET 的新模式，并可能提供一种靶向激酶耐药形式的途径，同时避免与广泛的激酶组抑制相关的潜在毒性问题。
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