Discovery of a Novel Series of Homo sapiens Caseinolytic Protease P Agonists for Colorectal Adenocarcinoma Treatment via ATF3-Dependent Integrated Stress Response

Homo sapiens caseinolytic
protease
P (HsClpP) activation is a promising strategy for colon cancer treatment.
In this study, CCG1423 was identified as a selective
activator of HsClpP. After optimization, NCA029 emerged
as the most potent compound, with an EC50 of 0.2 μM
against HsClpP. Molecular dynamics revealed that the affinity of NCA029 for the YYW aromatic network is crucial for its selectivity
toward HsClpP. Furthermore, NCA029 displayed favorable
pharmacokinetics and safety profiles and significantly inhibited tumor
growth in HCT116 xenografts, resulting in 83.6% tumor inhibition.
Mechanistically, NCA029 targeted HsClpP, inducing mitochondrial
dysfunction and activating the ATF3-dependent integrated stress response,
ultimately causing cell death in colorectal adenocarcinoma. These
findings highlight NCA029 as an effective HsClpP activator
with potential for colon cancer therapy.