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

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: IC₅₀ = 0.17 μM; NCA029: IC₅₀ = 5.04 μM), and H82 cells (8o: IC₅₀ = 0.19 μM; NCA029: IC₅₀ = 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 %.