Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase

doi:10.1016/j.bmcl.2007.09.007

Bioorganic & Medicinal Chemistry Letters

Volume 17, Issue 22, 15 November 2007, Pages 6280-6285

https://doi.org/10.1016/j.bmcl.2007.09.007 Get rights and content

Abstract

From HTS lead 1, a novel benzoisoquinolinone class of ATP-competitive Chk1 inhibitors was devised and synthesized via a photochemical route. Using X-ray crystallography as a guide, potency was rapidly enhanced through the installation of a tethered basic amine designed to interact with an acidic residue (Glu91) in the enzyme pocket. Further SAR was explored at the solvent front and near to the H1 pocket and resulted in the discovery of low MW, sub-nanomolar inhibitors of Chk1.

Graphical abstract

Benzoisoquinolinones (i.e., 55) are reported as potent inhibitors of Chk1 kinase.

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Citation Excerpt :
It is favored for the stable binding between ligands and protein. Previous studies have shown that ligand formed hydrogen bonds with Glu91 can potentially enhance the potency of the compound (Garbaccio et al., 2007). The interaction analysis showed that compound 2 and compound 3 formed hydrogen bonds with Glu91.
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Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase

Abstract

Graphical abstract

Drug Future

Pharmacol. Ther.

Nat. Rev. Cancer

Cancer Cell

Mol. Cancer Ther.

Recent Patent Anti-Cancer Drug Dis.

Anti-Cancer Agents in Med. Chem.