通过靶向ATP结合口袋的独特结构设计和合成强效且选择性的PIM激酶抑制剂
Design and Synthesis of Potent and Selective PIM Kinase Inhibitors by Targeting Unique Structure of ATP-Binding Pocket.
作者信息
Nakano Hirofumi, Hasegawa Tsukasa, Kojima Hirotatsu, Okabe Takayoshi, Nagano Tetsuo
机构信息
Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
出版信息
ACS Med Chem Lett. 2017 Apr 3;8(5):504-509. doi: 10.1021/acsmedchemlett.6b00518. eCollection 2017 May 11.
Abstract
In the development of kinase inhibitors, one of the major concerns is selectivity. An effective strategy to achieve high selectivity is to utilize structural differences among kinases to inform inhibitor design. Here, we set out to improve the PIM (proviral integration site for Moloney murine leukemia virus) kinase-inhibitory selectivity of our previously reported 7-azaindole derivative , which has promising ADMET properties, by targeting a unique bulge in the ATP-binding pocket. 6-Substituted 7-azaindoles, especially the 6-chlorinated derivatives, proved to be potent and selective PIM kinase inhibitors and appear to be promising lead compounds for future drug discovery.
摘要
在激酶抑制剂的研发过程中，主要关注点之一是选择性。实现高选择性的一种有效策略是利用激酶之间的结构差异来指导抑制剂设计。在此，我们着手通过靶向ATP结合口袋中的一个独特凸起，来提高我们先前报道的具有良好药物代谢动力学性质的7-氮杂吲哚衍生物对PIM（莫洛尼鼠白血病病毒前病毒整合位点）激酶的抑制选择性。事实证明，6-取代的7-氮杂吲哚，尤其是6-氯化衍生物，是强效且选择性的PIM激酶抑制剂，似乎是未来药物研发中很有前景的先导化合物。
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