Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States.
Division of Hematology/Oncology, University of California, San Francisco, California 94143, United States.
J Med Chem. 2024 Jun 27;67(12):9776-9788. doi: 10.1021/acs.jmedchem.3c01629. Epub 2024 Jun 5.
Type II kinase inhibitors bind in the "DFG-out" kinase conformation and are generally considered to be more potent and selective than type I inhibitors, which target a DFG-in conformation. Nine type II inhibitors are currently clinically approved, with more undergoing clinical development. Resistance-conferring secondary mutations emerged with the first series of type II inhibitors, most commonly at residues within the kinase activation loop and at the "gatekeeper" position. Recently, new inhibitors have been developed to overcome such mutations; however, mutations activating other pathways (and/or other targets) have subsequently emerged on occasion. Here, we systematically summarize the secondary mutations that confer resistance to type II inhibitors, the structural basis for resistance, newer inhibitors designed to overcome resistance, as well as the challenges and opportunities for the development of new inhibitors to overcome secondary kinase domain mutations.
II 型激酶抑制剂结合在“DFG-out”激酶构象中，通常被认为比靶向 DFG-in 构象的 I 型抑制剂更有效和更具选择性。目前有九种 II 型抑制剂获得临床批准，还有更多的正在进行临床开发。随着第一批 II 型抑制剂的出现，出现了耐药性赋予的继发突变，最常见于激酶激活环内和“守门员”位置的残基。最近，已经开发出了新的抑制剂来克服这些突变；然而，偶尔会出现激活其他途径（和/或其他靶点）的突变。在这里，我们系统地总结了赋予 II 型抑制剂耐药性的继发突变、耐药性的结构基础、旨在克服耐药性的新型抑制剂，以及开发新抑制剂克服继发激酶结构域突变的挑战和机遇。
