Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
J Biol Chem. 2021 Jan-Jun;296:100349. doi: 10.1016/j.jbc.2021.100349. Epub 2021 Jan 30.
The histone methyltransferase EZH2 has been the target of numerous small-molecule inhibitor discovery efforts over the last 10+ years. Emerging clinical data have provided early evidence for single agent activity with acceptable safety profiles for first-generation inhibitors. We have developed kinetic methodologies for studying EZH2-inhibitor-binding kinetics that have allowed us to identify a unique structural modification that results in significant increases in the drug-target residence times of all EZH2 inhibitor scaffolds we have studied. The unexpected residence time enhancement bestowed by this modification has enabled us to create a series of second-generation EZH2 inhibitors with sub-pM binding affinities. We provide both biophysical evidence validating this sub-pM potency and biological evidence demonstrating the utility and relevance of such high-affinity interactions with EZH2.
过去 10 多年来，组蛋白甲基转移酶 EZH2 一直是许多小分子抑制剂发现工作的目标。新兴的临床数据为第一代抑制剂的单药活性提供了早期证据，且具有可接受的安全性。我们已经开发出用于研究 EZH2 抑制剂结合动力学的动力学方法，这些方法使我们能够识别出一种独特的结构修饰，从而显著增加我们研究的所有 EZH2 抑制剂支架的药物靶标停留时间。这种修饰赋予的出人意料的停留时间增强使我们能够创建一系列具有亚皮摩尔结合亲和力的第二代 EZH2 抑制剂。我们提供了验证这种亚皮摩尔效力的生物物理证据，并提供了具有 EZH2 这种高亲和力相互作用的实用性和相关性的生物学证据。
