title: Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations.
abstract: Imatinib is an inhibitor of the Abl tyrosine kinase domain that is effective in the treatment of chronic myelogenic leukemia. Although imatinib binds tightly to the Abl kinase domain, its affinity for the closely related kinase domain of c-Src is at least 2,000-fold lower. Imatinib recognition requires a specific inactive conformation of the kinase domain, in which a conserved Asp-Phe-Gly (DFG) motif is flipped with respect to the active conformation. The inability of c-Src to readily adopt this flipped DFG conformation was thought to underlie the selectivity of imatinib for Abl over c-Src. Here, we present a series of inhibitors (DSA compounds) that are based on the core scaffold of imatinib but which bind with equally high potency to c-Src and Abl. The DSA compounds bind to c-Src in the DFG-flipped conformation, as confirmed by crystal structures and kinetic analysis. The origin of the high affinity of these compounds for c-Src is suggested by the fact that they also inhibit clinically relevant Abl variants bearing mutations in a structural element, the P-loop, that normally interacts with the phosphate groups of ATP but is folded over a substructure of imatinib in Abl. Importantly, several of the DSA compounds block the growth of Ba/F3 cells harboring imatinib-resistant BCR-ABL mutants, including the Thr315Ile "gatekeeper" mutation, but do not suppress the growth of parental Ba/F3 cells.
authors.affiliation: Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkely, USA.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Seeliger
authors.forename: Pratistha
authors.initials: P
authors.lastname: Ranjitkar
authors.forename: Corynn
authors.initials: C
authors.lastname: Kasap
authors.forename: Yibing
authors.initials: Y
authors.lastname: Shan
authors.forename: David E
authors.initials: DE
authors.lastname: Shaw
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Maly
mesh_terms: D000818:Animals; D001549:Benzamides; D000081247:CSK Tyrosine-Protein Kinase; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019061:src-Family Kinases
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases; C000631346:CSK protein, human