Design, synthesis and biological evaluation of 1H-pyrazolo [3,4-d]pyrimidine derivatives as PAK1 inhibitors that trigger apoptosis, ER stress and anti...

ID: ALA4765282

Journal: Eur J Med Chem

Title: Design, synthesis and biological evaluation of 1H-pyrazolo [3,4-d]pyrimidine derivatives as PAK1 inhibitors that trigger apoptosis, ER stress and anti-migration effect in MDA-MB-231 cells.

Authors: Zhang J,Zou L,Tang P,Pan D,He Z,Yao D

Abstract: P21-activated kinase 1 (PAK1) is associated with cell proliferation, survival and migration. Deregulation of PAK1 activity is involved in various human diseases, including cancer, inflammation, and neurological disorders. Using a high-throughput virtual screening, we identified the 1H-pyrazolo [3,4-d]pyrimidine scaffold as a promising lead for targeting PAK1. We designed and synthesized a focused library through a structure-based strategy. A novel potent PAK1 inhibitor, ZMF-10, was discovered, which presented an IC value of 174 nM with a good selectivity. In addition, ZMF-10 could inhibit PAK1-ERK signaling to suppress MDA-MB-231 cells proliferation with an IC value of 3.48 μM for 48 h. Subsequently, ZMF-10 was documented to induce cell apoptosis. Interestingly, according to the RNASeq-based analyses, we substantiated that ZMF-10 induced significant ER-Stress, suppressed migration via FOXO3 activation, JNK1/2, ERK1/2 and AKT signaling inhibition. Together, these results demonstrate that ZMF-10 is a novel PAK1 inhibitor triggering apoptosis, ER stress and anti-migration effect in MDA-MB-231 cells, which may provide a candidate lead for the development of novel potent inhibitors of PAK1.

CiteXplore: 32222676

DOI: 10.1016/j.ejmech.2020.112220

Patent ID: ┄