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

Abstract

The activation of <i>Homo sapiens</i> 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 <b>ONC201</b>. Here, a novel class of HsClpP agonists is designed and synthesized using a ring-opening strategy based on the lead compound <b>1</b> reported in our previous study. Among these novel scaffold agonists, compound <b>7k</b> exhibited remarkably enhanced proteolytic activity of HsClpP (EC₅₀ = 0.79 ± 0.03 μM) and antitumor activity <i>in vitro</i> (IC₅₀ = 0.038 ± 0.003 μM). Moreover, the intraperitoneal administration of compound <b>7k</b> markedly suppressed tumor growth in Mv4-11 xenograft models, achieving a tumor growth inhibition rate of 88%. Concurrently, <b>7k</b> displayed advantageous pharmacokinetic properties <i>in vivo</i>. This study underscores the promise of compound <b>7k</b> as a significant HsClpP agonist and an antileukemia drug candidate, warranting further exploration for AML treatment.