title: AP24163 inhibits the gatekeeper mutant of BCR-ABL and suppresses in vitro resistance.
abstract: Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukaemia. The second generation BCR/ABL inhibitors nilotinib and dasatinib effectively inhibit most imatinib resistance variants, but are ineffective against the gatekeeper mutant, T315I. Gatekeeper mutation activates the kinase by stabilizing the hydrophobic spine. Here, we describe that the rationally designed compound AP24163 can inhibit native and gatekeeper mutants of the BCR/ABL kinase. Structural modelling suggests that AP24163 affects the flexibility of the P-loop and destabilizes the active conformation by disrupting the hydrophobic spine. In vitro screening for drug resistance identified clones with compound mutations involving both the P-loop and T315I. Our studies provide structural insights for the design of inhibitors against the gatekeeper mutant and suggest that up-front combination therapy may be required to prevent the emergence of compound-resistant mutations.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, The Children's Hospital, Dana Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Azam
authors.forename: John T
authors.initials: JT
authors.lastname: Powers
authors.forename: William
authors.initials: W
authors.lastname: Einhorn
authors.forename: Wei-Sheng
authors.initials: WS
authors.lastname: Huang
authors.forename: William C
authors.initials: WC
authors.lastname: Shakespeare
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhu
authors.forename: David
authors.initials: D
authors.lastname: Dalgarno
authors.forename: Tim
authors.initials: T
authors.lastname: Clackson
authors.forename: Tomi K
authors.initials: TK
authors.lastname: Sawyer
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D051379:Mice; D009154:Mutation; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: C548138:AP 24163; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000225:Adenine; D000069439:Dasatinib