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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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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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 |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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