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Bioorg Med Chem Lett. 2012 Apr 1;22(7):2609-12. doi: 10.1016/j.bmcl.2012.01.110. Epub 2012 Feb 9.

Pyridyl aminothiazoles as potent inhibitors of Chk1 with slow dissociation rates.

Author information

1
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. vadim_dudkin@merck.com

Abstract

Pyridyl aminothiazoles comprise a novel class of ATP-competitive Chk1 inhibitors with excellent inhibitory potential. Modification of the core with ethylenediamine amides provides compounds with low picomolar potency and very high residence times. Investigation of binding parameters of such compounds using X-ray crystallography and molecular dynamics simulations revealed multiple hydrogen bonds to the enzyme backbone as well as stabilization of the conserved water molecules network in the hydrophobic binding region.

PMID:
22374217
DOI:
10.1016/j.bmcl.2012.01.110
[Indexed for MEDLINE]

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