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X‐ray structures of checkpoint kinase 2 in complex with inhibitors that target its gatekeeper‐dependent hydrophobic pocket
Author(s) -
Lountos George T.,
Jobson Andrew G.,
Tropea Joseph E.,
Self Christopher R.,
Zhang Guangtao,
Pommier Yves,
Shoemaker Robert H.,
Waugh David S.
Publication year - 2011
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2011.08.050
Subject(s) - chemistry , kinase , x ray , biophysics , cancer research , biochemistry , biology , physics , optics
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 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.