Assadieskandar Amir, Yu Caiqun, Maisonneuve Pierre, Liu Xu, Chen Ying-Chu, Prakash G K Surya, Kurinov Igor, Sicheri Frank, Zhang Chao
Loker Hydrocarbon Research Institute & Department of Chemistry, University of Southern California, University Park, Los Angeles, CA 90089, USA.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Eur J Med Chem. 2018 Feb 25;146:519-528. doi: 10.1016/j.ejmech.2018.01.053. Epub 2018 Jan 31.
Established strategies for discovering selective kinase inhibitors are target-centric as they often target certain structural or reactive features in the target kinase. In the absence of such prominent features, there is a lack of general methods for discovering selective inhibitors. Here we describe a new strategy that exploits conformational flexibility of kinases for achieving selective kinase inhibition. Through ring closure, we designed and synthesized a panel of isoquinoline-containing compounds as rigidified analogs of an amidophenyl-containing parent compound. These analogs potently inhibit kinases including Abl and BRAF but have diminished inhibition against some other kinases compared to the parent compound. Sequence analysis reveals that many of the kinases that are potently inhibited by the isoquonoline-containing compounds contain a long insertion within their catalytic domains. A crystal structure of one rigid compound bound to BRAF confirmed its binding mode. Our findings highlight the potential of a novel strategy of rigidification for improving the selectivity of kinase inhibitors.
已确立的发现选择性激酶抑制剂的策略是以靶点为中心的，因为它们通常针对目标激酶中的某些结构或反应性特征。在缺乏此类显著特征的情况下，缺乏发现选择性抑制剂的通用方法。在此，我们描述了一种利用激酶的构象灵活性来实现选择性激酶抑制的新策略。通过闭环，我们设计并合成了一组含异喹啉的化合物，作为含酰胺苯基母体化合物的刚性类似物。与母体化合物相比，这些类似物能有效抑制包括Abl和BRAF在内的激酶，但对其他一些激酶的抑制作用减弱。序列分析表明，许多被含异喹啉化合物有效抑制的激酶在其催化结构域内含有一个长插入片段。一种与BRAF结合的刚性化合物的晶体结构证实了其结合模式。我们的发现突出了刚性化这一新颖策略在提高激酶抑制剂选择性方面的潜力。
