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Ref Type Journal Article
PMID (32222676)
Authors Zhang J, Zou L, Tang P, Pan D, He Z, Yao D
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.
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Abstract Text 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 IC50 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 IC50 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
ZMF-10 ZMF-10 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
ZMF-10 ZMF10|ZMF 10 PAK1 Inhibitor 11 ZMF-10 is an inhibitor of PAK1, potentially inhibiting downstream signaling, inducing tumor cell apoptosis and inhibiting tumor cell proliferation and migration (PMID: 32222676).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References