RAPT Therapeutics, Inc., 561 Eccles Avenue, South San Francisco, California 94080, United States.
Schrödinger, 120 West 45th Street, New York, New York 10036, United States.
J Med Chem. 2020 May 28;63(10):5398-5420. doi: 10.1021/acs.jmedchem.0c00245. Epub 2020 May 6.
USP7 is a promising target for cancer therapy as its inhibition is expected to decrease function of oncogenes, increase tumor suppressor function, and enhance immune function. Using a structure-based drug design strategy, a new class of reversible USP7 inhibitors has been identified that is highly potent in biochemical and cellular assays and extremely selective for USP7 over other deubiquitinases. The succinimide was identified as a key potency-driving motif, forming two strong hydrogen bonds to the allosteric pocket of USP7. Redesign of an initial benzofuran-amide scaffold yielded a simplified ether series of inhibitors, utilizing acyclic conformational control to achieve proper amine placement. Further improvements were realized upon replacing the ether-linked amines with carbon-linked morpholines, a modification motivated by free energy perturbation (FEP+) calculations. This led to the discovery of compound , a highly potent, selective, and orally bioavailable USP7 inhibitor. In xenograft studies, compound demonstrated tumor growth inhibition in both p53 wildtype and p53 mutant cancer cell lines, demonstrating that USP7 inhibitors can suppress tumor growth through multiple different pathways.
USP7 是癌症治疗的一个有前途的靶点，因为其抑制作用有望降低癌基因的功能，增加肿瘤抑制因子的功能，并增强免疫功能。采用基于结构的药物设计策略，已经鉴定出一类新型的可逆 USP7 抑制剂，在生化和细胞测定中具有很高的活性，对 USP7 的选择性远远超过其他去泛素化酶。琥珀酰亚胺被确定为一个关键的效力驱动基序，与 USP7 的变构口袋形成两个强氢键。对初始苯并呋喃酰胺支架进行重新设计，得到了简化的醚系列抑制剂，利用无环构象控制来实现适当的胺定位。在用碳连接的吗啉取代醚连接的胺后，进一步得到了改进，这一修饰是受到自由能微扰（FEP+）计算的启发。这导致了化合物的发现，它是一种高效、选择性和可口服生物利用的 USP7 抑制剂。在异种移植研究中，化合物在 p53 野生型和 p53 突变型癌细胞系中均显示出肿瘤生长抑制作用，表明 USP7 抑制剂可以通过多种不同的途径抑制肿瘤生长。
