Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 2, Pages 827-846Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01815
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Funding
- NIH/NCI [R01CA148706]
- NIH [1S10OD010678-01, 1S10RR026377-01]
- University of Tennessee College of Pharmacy Drug Discovery Center
- National Major Scientific and Technological Special Project (Significant New Drugs Development) [2018ZX09201018-021]
- American Lebanese Syrian Associated Charities (ALSAC)
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We recently reported the crystal structure of tubulin in complex with a colchicine binding site inhibitor (CBSI), ABI-231, having 2-aryl-4-benzoyl-imidazole (ABI). Based on this and additional crystal structures, here we report the structure-activity relationship study of a novel series of pyridine analogues of ABI-231, with compound 4v being the most potent one (average IC50 similar to 1.8 nM) against a panel of cancer cell lines. We determined the crystal structures of another potent CBSI ABI-274 and 4v in complex with tubulin and confirmed their direct binding at the colchicine site. 4v inhibited tubulin polymerization, strongly suppressed A375 melanoma tumor growth, induced tumor necrosis, disrupted tumor angiogenesis, and led to tumor cell apoptosis in vivo. Collectively, these studies suggest that 4v represents a promising new generation of tubulin inhibitors.
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