Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently reported that CMPD1, originally developed as an inhibitor of MK2 activation, primarily inhibits tubulin polymerisation and induces apoptosis in glioblastoma cells. In the present study we provide detailed pharmacological investigation of CMPD1 analogues with improved molecular properties. We determined their anti-cancer efficacy in glioblastoma cells with enhanced EGFR signalling, as deregulated EGFR often leads to chemoresistance. Eight analogues of CMPD1 with varying lipophilicity and basicity were synthesised and tested for efficacy in the cell viability assay using established glioblastoma cell lines and patient-derived primary glioblastoma cells. The mechanism of action for the most potent analogue 15 was determined using MK2 activation and tubulin polymerisation assays, together with the immunofluorescence analysis of the mitotic spindle formation. Apoptosis was analysed by Annexin V staining, immunoblotting analysis of bcl-2 proteins and PARP cleavage. The apoptotic activity of CMPD1 and analogue 15 was comparable across glioblastoma cell lines regardless of the EGFR status. Primary glioblastoma cells of the classical subtype that are characterized by enhanced EGFR activity were most sensitive to the treatment with CMPD1 and 15. In summary, we present mechanism of action for a novel small molecule tubulin inhibitor, compound 15 that inhibits tubulin polymerisation and mitotic spindle formation, induces degradation of anti-apoptotic bcl-2 proteins and leads to apoptosis of glioblastoma cells. We also demonstrate that the enhanced EGFR activity does not decrease the efficacy of tubulin inhibitors developed in this study.
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PMID:Pharmacology of novel small-molecule tubulin inhibitors in glioblastoma cells with enhanced EGFR signalling. 2651 52

Gastric cancer is a common cancer in the world with high morbidity and mortality. Here, we report that FPHPB (4-(4-(2-fluoropyridin-3-yl)phenyl)-N-(4-hydroxyphenyl)), a derivative of CMPD-1/MK2a Inhibitor, had anti-tumor activities by inhibiting gastric tumor SNU-16 and SGC7901 cells. FPHPB dose-dependently inhibited cell proliferation, induced cell apoptosis and arrested SNU-16 and SGC7901 cells in G2-M cell cycle checkpoint. Upon treatment with FPHPB, apoptotic proteins cleaved PARP and cleaved caspase-3 were remarkably increased, and G2-M regulatory molecules, the phosphorylation of Cdc2 and Chk2, were significantly accentuated. Collectively, FPHPB has anti-tumor activities and may be a potential candidate for treating gastric cancers.
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PMID:FPHPB inhibits gastric tumor cell proliferation by inducing G2-M cell cycle arrest. 2930 95