X-ray structures of checkpoint kinase 2 in complex with inhibitors that target its gatekeeper-dependent hydrophobic pocket

Journal Article · Mon Sep 17 04:00:00 EDT 2012 · FEBS Lett.

DOI:https://doi.org/10.1016/j.febslet.2011.08.050· OSTI ID:1040906

Lountos, George T; Jobson, Andrew G; Tropea, Joseph E; Self, Christopher R; Zhang, Guangtao; Pommier, Yves; Shoemaker, Robert H; Waugh, David S ^[1]

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1. Provid

The serine/threonine checkpoint kinase 2 (Chk2) is an attractive molecular target for the development of small molecule inhibitors to treat cancer. Here, we report the rational design of Chk2 inhibitors that target the gatekeeper-dependent hydrophobic pocket located behind the adenine-binding region of the ATP-binding site. These compounds exhibit IC{sub 50} values in the low nanomolar range and are highly selective for Chk2 over Chk1. X-ray crystallography was used to determine the structures of the inhibitors in complex with the catalytic kinase domain of Chk2 to verify their modes of binding.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: OTHERNIHNCI
• OSTI ID: 1040906
• Journal Information: FEBS Lett., Journal Name: FEBS Lett. Journal Issue: (20) ; 10, 2011 Vol. 585; ISSN 0014-5793; ISSN FEBLAL
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
CRYSTALLOGRAPHY
DESIGN
NEOPLASMS
PHOSPHOTRANSFERASES
TARGETS