Hit to Lead optimization of a novel class of squarate-containing polo-like kinases inhibitors
2012
Abstract A high throughput screening (HTS) hit, 1 (Plk1 K i = 2.2 μM) was optimized and evaluated for the enzymatic inhibition of Plk-1 kinase. Molecular modeling suggested the importance of adding a hydrophobic aromatic amine side chain in order to improve the potency by a classic kinase H-donor–acceptor binding mode. Extensive SAR studies led to the discovery of 49 (Plk1 K i = 5 nM; EC 50 = 1.05 μM), which demonstrated moderate efficacy at 100 mpk in a MiaPaCa tumor model, with no overt toxicity.
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