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Bioorg Med Chem Lett. 2012 Dec 15;22(24):7615-22. doi: 10.1016/j.bmcl.2012.10.009. Epub 2012 Oct 11.

Hit to Lead optimization of a novel class of squarate-containing polo-like kinases inhibitors.

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Medicinal Chemistry Technologies and Structural Biology, Global Pharmaceutical Research & Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA.


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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