Rational Design of a Novel Class of Human ClpP Agonists through a Ring-Opening Strategy with Enhanced Antileukemia Activity.

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.