Discovery Chemistry, ‡Discovery Technologies, §Discovery Oncology, ∥Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
J Med Chem. 2013 Jul 25;56(14):5979-83. doi: 10.1021/jm400487c. Epub 2013 Jul 16.
Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.
恢复 p53 活性抑制 p53-MDM2 相互作用被认为是一种有吸引力的癌症治疗方法。然而，疏水的蛋白-蛋白相互作用表面代表了开发具有理想药理特性的小分子抑制剂的重大挑战。RG7112 是第一个进入临床开发的小分子 p53-MDM2 抑制剂。在这里，我们报告了第二代临床 MDM2 抑制剂 RG7388 的发现和特性，其具有更高的效力和选择性。
