Discovery of Activators of Human Caseinolytic Protease P with a Benzolactam Scaffold

Based on compound 1, a previously identified
activator
of human caseinolytic protease P (hClpP) containing a pyrazololactam
scaffold, a class of benzolactam derivatives was designed through
a scaffold-hopping strategy. Structural optimization of this series
led to the identification of LZL25, which potently activated
recombinant hClpP with an EC50 of 0.36 μM and inhibited
the growth of MDA-MB-231 cells with an IC50 of 0.29 μM.
Mechanistic studies showed that LZL25 strongly bound
to and activated cellular hClpP, effectively promoted the degradation
of hClpP substrates in cells, and robustly induced apoptosis in MDA-MB-231
cells. Further optimization yielded LZL50, which demonstrated
favorable pharmacokinetic properties and exhibited potent antitumor
activity in an MDA-MB-231 xenograft mouse model.