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Use of cMet Crystal Structures to Identify Potential Drug‐Resistant Mutants
Author(s) -
Meyer Sheryl Lynne,
Pauletti Daniel,
Husten Jean,
Federov Alexander,
Herbertz Torsten,
Federov Elena,
Underiner Ted L.,
Wells Gregory J.,
Weinberg Linda R.,
Milkiewicz Karen L.,
Dorsey Bruce D.,
Almo Steven C.,
Ator Mark A.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.676.9
Subject(s) - mutant , enzyme , allosteric regulation , chemistry , kinase , drug , mutation , tyrosine kinase , biochemistry , biology , receptor , pharmacology , gene
For Oncology drugs targeted to tyrosine kinases, drug‐resistance often occurs from selection of cells harboring mutations in the kinase domain of the target. The identification of potential drug‐resistant mutants in advance of patient treatment allows for early design of second‐generation drugs that retain selectivity for these mutants. Towards this goal, co‐crystal structures of two diverse inhibitors were generated. Based on these structures, 11 mutants at 5 positions within the ATP pocket were examined. The kinetic parameters for the mutants were compared to wild‐type (WT) for both the basal and activated enzyme forms. Numerous differences were observed, but most notably the activated M1229 and Y1230 mutants had elevated catalytic efficiencies relative to WT. Two distinct inhibitors were studied against this panel, the oxindole SU11274 and the diaminopyrimidine compound 1. Two mutants (I1084L, M1229I) had higher affinity than WT for both inhibitors in both conformations and the gatekeeper L1157I mutant had substantially lower affinity. SU11274 also had reduced affinity for Y1230 and D1228 mutants, whereas the shifts were much less pronounced with compound 1. These data expand the repertoire of mutations in the ATP pocket that retain or enhance enzymatic activity and show that these mutants can display divergent effects on the potency of inhibitors from different chemical series.