State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
Laboratory of Human Diseases and Immunotherapies, West China Hospital and Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
J Med Chem. 2024 Apr 25;67(8):6769-6792. doi: 10.1021/acs.jmedchem.4c00338. Epub 2024 Apr 15.
The activation of Casein lysing protease P (HsClpP) by a chemical or genetic strategy has been proved to be a new potential therapy in acute myeloid leukemia (AML). However, limited efficacy has been achieved with classic agonist imipridone . Here, a novel class of HsClpP agonists is designed and synthesized using a ring-opening strategy based on the lead compound reported in our previous study. Among these novel scaffold agonists, compound exhibited remarkably enhanced proteolytic activity of HsClpP (EC = 0.79 ± 0.03 μM) and antitumor activity (IC = 0.038 ± 0.003 μM). Moreover, the intraperitoneal administration of compound markedly suppressed tumor growth in Mv4-11 xenograft models, achieving a tumor growth inhibition rate of 88%. Concurrently, displayed advantageous pharmacokinetic properties . This study underscores the promise of compound as a significant HsClpP agonist and an antileukemia drug candidate, warranting further exploration for AML treatment.
通过化学或遗传策略激活 Caspase 溶酶体蛋白酶 P（HsClpP）已被证明是急性髓细胞白血病（AML）的一种新的潜在治疗方法。然而，经典激动剂异丙嗪的疗效有限。在这里，我们使用基于我们之前研究中报道的先导化合物的开环策略设计和合成了一类新型 HsClpP 激动剂。在这些新型支架激动剂中，化合物表现出显著增强的 HsClpP 蛋白水解活性（EC = 0.79 ± 0.03 μM）和抗肿瘤活性（IC = 0.038 ± 0.003 μM）。此外，化合物腹腔给药能显著抑制 Mv4-11 异种移植模型中的肿瘤生长，肿瘤生长抑制率达到 88%。同时，化合物显示出有利的药代动力学特性。这项研究强调了化合物作为一种有效的 HsClpP 激动剂和白血病药物候选物的潜力，值得进一步探索用于 AML 的治疗。
