一种新型PSMA-PI3K小分子药物偶联物的设计、合成及生物学评价。
Design, synthesis and biological evaluation of a novel PSMA-PI3K small molecule drug conjugate.
作者信息
Peng Shouguo, Li Haixia, Cui Weilu, Xiong Tianning, Hu Jiaqi, Qi Haixiang, Lin Songwen, Wu Deyu, Ji Ming, Xu Heng
机构信息
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China
Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China.
出版信息
RSC Med Chem. 2024 Aug 24;15(10):3485-94. doi: 10.1039/d4md00246f.
Small molecule drug conjugates are an emerging targeted therapy for cancer treatment. Building upon the overexpressed prostate-specific membrane antigen (PSMA) in prostate cancer, we herein report the design and synthesis of a novel PSMA-PI3K small molecule drug conjugate 1. Conjugate 1 demonstrates potent inhibition against PI3K with an IC value of 0.40 nM and simultaneously targets PSMA, giving rise to selective growth inhibition activity for PSMA-positive cancer cells. Conjugate 1 also potently inhibits the phosphorylation of PI3K main downstream effectors and arrests the cell cycle in the G0/G1 phase in PSMA-positive 22Rv1 prostate cancer cells. Further evaluation shows that conjugate 1 has favorable efficacy and tolerability in a 22Rv1 xenograft model, demonstrating its potential application in targeted cancer therapy.
小分子药物偶联物是一种新兴的癌症靶向治疗方法。基于前列腺癌中过表达的前列腺特异性膜抗原（PSMA），我们在此报告了一种新型PSMA-PI3K小分子药物偶联物1的设计与合成。偶联物1对PI3K具有强效抑制作用，IC值为0.40 nM，同时靶向PSMA，对PSMA阳性癌细胞产生选择性生长抑制活性。偶联物1还能有效抑制PI3K主要下游效应物的磷酸化，并使PSMA阳性的22Rv1前列腺癌细胞的细胞周期停滞在G0/G1期。进一步评估表明，偶联物1在22Rv1异种移植模型中具有良好的疗效和耐受性，证明了其在癌症靶向治疗中的潜在应用。
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