ECB-ART-45070
Bioorg Med Chem
2017 Jan 15;252:658-664. doi: 10.1016/j.bmc.2016.11.041.
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3-Amino-thieno[2,3-b]pyridines as microtubule-destabilising agents: Molecular modelling and biological evaluation in the sea urchin embryo and human cancer cells.
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A series of 3-amino-thieno[2,3-b]pyridines was prepared and tested in a phenotypic sea urchin embryo assay to identify potent and specific molecules that affect tubulin dynamics. The most active compounds featured a tricyclic core ring system with a fused cycloheptyl or cyclohexyl substituent and unsubstituted or alkyl-substituted phenyl moiety tethered via a carboxamide. Low nano-molar potency was observed in the sea urchin embryos for the most active compounds (1-5) suggestive of a microtubule-destabilising effect. The molecular modelling studies indicated that the tubulin colchicine site is inhibited, which often leads to microtubule-destabilisation in line with the sea urchin embryo results. Finally, the identified hits displayed a robust growth inhibition (GI50 of 50-250nM) of multidrug-resistant melanoma MDA-MB-435 and breast MDA-MB-468 human cancer cell lines. This work demonstrates that for the thieno[2,3-b]pyridines the most effective mechanism of action is microtubule-destabilisation initiated by binding to the colchicine pocket.
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Genes referenced: LOC100887844 LOC100893907 LOC115919910 stk36 tubgcp2