Work

A shape complementarity strategy based on NCA029 enables potent HsClpP agonists for the treatment of small cell lung carcinoma

Year: 2025

Type: article

Abstract: Owing to its essential role in maintaining mitochondrial homeostasis, activation of HsClpP is potentially a promising strategy for treating a wide range of cancers, including small cell lung carcinoma (SCLC). In this work, by using a shape complementarity strategy, we designed and synthesized a series of HsClpP agonist based on NCA029, a non-imipridone HsClpP agonist identified in our previous work. Among these derivatives, compound 8o exhibited approximately 5-fold greater binding affinity than NCA029 with HsClpP due to attachment of an additional ring structure at the β-position of NCA029's double bond. It potently inhibited SCLC cells, such as H69 cells ( 8o : IC 50 = 0.17 μM; NCA029: IC 50 = 5.04 μM), and H82 cells ( 8o : IC 50 = 0.19 μM; NCA029: IC 50 = 1.04 μM). In addition, 8o exerted improved safety profiles than NCA029 in vitro and in vivo. Furthermore, compound 8o , which exhibits favorable pharmacokinetic properties, significantly inhibited tumor growth in non-SMC xenograft models, achieving a tumor growth inhibition rate of up to 63.01 %.

Source: European Journal of Medicinal Chemistry

DOI: 10.1016/j.ejmech.2025.118008