7vp9

Publication Abstract from PubMed

The mitochondrial caseinolytic protease P (ClpP) is a target candidate for treating leukemia; however, the effects of ClpP modulation on solid tumors have not been adequately explored. Here, we report a potent activator of ClpP with the therapeutic potential for pancreatic ductal adenocarcinoma (PDAC). We first validated that aberrant ClpP activation leads to growth arrest of PDAC cells and tumors. We then performed high-throughput screening and synthetic optimization, from which we identified ZG111, a potent activator of ClpP. ZG111 binds to ClpP and promotes the ClpP-mediated degradation of respiratory chain complexes. This degradation activates the JNK/c-Jun pathway, induces the endoplasmic reticulum stress response, and consequently causes the growth arrest of PDAC cells. ZG111 also produces inhibitory effects on tumor growth in cell line-derived and patient-derived xenograft mouse models. Altogether, our data demonstrate a promising therapeutic strategy for PDAC suppression through the chemical activation of ClpP.

Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma.,Wang P, Zhang T, Wang X, Xiao H, Li H, Zhou LL, Yang T, Wei B, Zhu Z, Zhou L, Yang S, Lu X, Zhang Y, Huang Y, Gan J, Yang CG Cell Chem Biol. 2022 Jul 20. pii: S2451-9456(22)00245-8. doi:, 10.1016/j.chembiol.2022.07.002. PMID:35905743^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.