化学
结合
谷氨酸羧肽酶Ⅱ
前列腺特异性抗原
小分子
毒性
药品
药理学
奥拉帕尼
抗原
前列腺癌
组合化学
生物化学
内科学
免疫学
酶
医学
数学分析
数学
有机化学
癌症
聚合酶
聚ADP核糖聚合酶
作者
Qi Chen,Zhenying Wu,Haiying Zhu,Feng Zhang,Yongping Yu,Wenteng Chen
标识
DOI:10.1021/acs.jmedchem.4c01910
摘要
PARP inhibitors have gained attention in the treatment of metastatic castration-resistant prostate cancer, but approximately half of patients have to abort treatment due to severe hematological toxicity. Herein, we proposed a prostate-specific membrane antigen (PSMA)-targeting small molecule–drug conjugate (SMDC) strategy to address this issue. This led to CQ-16, which achieved its targeting to prostate tumor cells through binding to PSMA. Also, CQ-16 retained the PARP inhibitory activity and exhibited highly selective antiproliferative activities between PSMA-positive and PSMA-negative prostate cells. Moreover, the hematological toxicity observed in Olaparib was not showing in the group of CQ-16 even at a high dose of 390 mg/kg. Moreover, oral administration of CQ-16 exerted significant tumor growth inhibition in the 22Rv1 xenograft mouse model. These above findings not only highlight the potential of CQ-16 to overcome the hematological toxicity associated with PARP inhibitors but also provide a strategy to develop an SMDC with enhanced safety profiles.
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