Department of Medicinal Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States.
ACS Chem Biol. 2012 Nov 16;7(11):1910-7. doi: 10.1021/cb300337u. Epub 2012 Sep 5.
We have developed the first irreversible inhibitors of wild-type c-Src kinase. We demonstrate that our irreversible inhibitors display improved potency and selectivity relative to that of their reversible counterparts. Our strategy involves modifying a promiscuous kinase inhibitor with an electrophile to generate covalent inhibitors of c-Src. We applied this methodology to two inhibitor scaffolds that exhibit increased cellular efficacy when rendered irreversible. In addition, we have demonstrated the utility of irreversible inhibitors in studying the conformation of an important loop in kinases that can control inhibitor selectivity and cause drug resistance. Together, we have developed a general and robust framework for generating selective irreversible inhibitors from reversible, promiscuous inhibitor scaffolds.
我们开发了首个野生型 c-Src 激酶不可逆抑制剂。我们证明，与相应的可逆抑制剂相比，我们的不可逆抑制剂具有更好的活性和选择性。我们的策略包括用亲电试剂修饰一个广谱激酶抑制剂，从而生成 c-Src 的共价抑制剂。我们将这种方法应用于两种抑制剂骨架，当它们不可逆时，会提高细胞效力。此外，我们还证明了不可逆抑制剂在研究激酶中一个重要环的构象的有用性，该环可以控制抑制剂的选择性并导致耐药性。总之，我们已经开发出一种通用且稳健的框架，可从可逆的、广谱的抑制剂骨架中生成选择性的不可逆抑制剂。
