Rational Design of a Novel Class of Human ClpP Agonists through a Ring-Opening Strategy with Enhanced Antileukemia Activity
Xinrong Xiang, Zhengyi Dai, Baozhu Luo, Ninglin Zhao, Song Liu, Jing Sui, Jiasheng Huang, Yuanzheng Zhou, Jinlong Gu, Jiangnan Zhang, Tao Yang, Rui Bao, Youfu Luo
Abstract
The activation of Homo sapiens 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 ONC201 . Here, a novel class of HsClpP agonists is designed and synthesized using a ring-opening strategy based on the lead compound 1 reported in our previous study. Among these novel scaffold agonists, compound 7k exhibited remarkably enhanced proteolytic activity of HsClpP (EC 50 = 0.79 ± 0.03 μM) and antitumor activity in vitro (IC 50 = 0.038 ± 0.003 μM). Moreover, the intraperitoneal administration of compound 7k markedly suppressed tumor growth in Mv4-11 xenograft models, achieving a tumor growth inhibition rate of 88%. Concurrently, 7k displayed advantageous pharmacokinetic properties in vivo . This study underscores the promise of compound 7k as a significant HsClpP agonist and an antileukemia drug candidate, warranting further exploration for AML treatment.