The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: a structural analysis of the binding interactions of Gleevec, Nexavar, and BIRB-796.
The majority of kinase inhibitors developed to date are competitive inhibitors that target the ATP binding site; however, recent crystal structures of Gleevec (imatinib mesylate, STI571, PDB: 1IEP), Nexavar (Sorafenib tosylate, BAY 43-9006, PDB: 1UWJ), and BIRB-796 (PDB: 1KV2) have revealed a secondary binding site adjacent to the ATP binding site known as the DFG-out allosteric binding site. The recent successes of Gleevec and Nexavar for the treatment of chronic myeloid leukemia and renal cell carcinoma has generated great interest in the development of other kinase inhibitors that target this secondary binding site. Here, we present a structural comparison of the important and similar interactions necessary for Gleevec(R), Nexavar, and BIRB-796 to bind to their respective DFG-out allosteric binding pockets and the selectivity of each with respect to c-Abl, B-Raf, and p38alpha. A structural analysis of their selectivity profiles has been generated from the synthesis and evaluation of 8 additional DFG-out allosteric inhibitors that were developed directly from fragments of these successful scaffolds.
Dietrich
Justin
J
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85719, United States.
Hulme
Christopher
C
Hurley
Laurence H
LH
D000255:Adenosine Triphosphate / Q000737:chemistry; D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides; D001557:Benzenesulfonates / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D006860:Hydrogen Bonding; D000068877:Imatinib Mesylate; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology; D009536:Niacinamide / Q000031:analogs & derivatives; D009842:Oligopeptides / Q000737:chemistry*; D010671:Phenylurea Compounds; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D000077157:Sorafenib
D000970:Antineoplastic Agents; D001549:Benzamides; D001557:Benzenesulfonates; C553185:DFG peptide; D009281:Naphthalenes; D009842:Oligopeptides; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D000077157:Sorafenib; D016315:Proto-Oncogene Proteins c-abl; D048493:Proto-Oncogene Proteins B-raf; D048308:Mitogen-Activated Protein Kinase 14; C452139:doramapimod