发现N-苄基哌啶醇衍生物作为针对血液学的USP7抑制剂。
Discovery of N-Benzylpiperidinol derivatives as USP7 inhibitors against Hematology.
作者信息
Pan Youlu, Chen Haifeng, Fu Jingfeng, Zhang Jingyu, Wang Peipei, Chen Runmei, Geng Shuangshuang, Che Jinxin, Dong Xiaowu, Zhou Yubo, Huang Wenhai
机构信息
Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou 310058, China.
Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
出版信息
Bioorg Chem. 2024 Dec;153:107807. doi: 10.1016/j.bioorg.2024.107807. Epub 2024 Sep 12.
USP7 has been recognized as a potential target for the treatment of hematologic malignancies by stabilizing multiple cancer-relevant proteins. Nevertheless, drug-like USP7 inhibitors are still lacking. Herein, compound J21 (USP7 IC: 41.35 ± 2.16 nM) was discovered based on the structure of L55 and its co-crystal complex with USP7. Additionally, J21 exhibited greater metabolic stability (T: 1.25 h, C: 394.1 ± 48.3 ng/mL, and AUC: 597.8 ± 44.8 ng/mL∙h) compared to L55. These findings may further pave the way for the development of USP7 inhibitors for the treatment of hematologic malignancies.
通过稳定多种与癌症相关的蛋白质，USP7已被公认为是治疗血液系统恶性肿瘤的潜在靶点。然而，仍缺乏类似药物的USP7抑制剂。在此，基于L55的结构及其与USP7的共晶体复合物，发现了化合物J21（USP7 IC：41.35±2.16 nM）。此外，与L55相比，J21表现出更高的代谢稳定性（T：1.25小时，C：394.1±48.3 ng/mL，AUC：597.8±44.8 ng/mL∙h）。这些发现可能为开发用于治疗血液系统恶性肿瘤的USP7抑制剂进一步铺平道路。
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