title: AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.
abstract: Inhibition of BCR-ABL by imatinib induces durable responses in many patients with chronic myeloid leukemia (CML), but resistance attributable to kinase domain mutations can lead to relapse and a switch to second-line therapy with nilotinib or dasatinib. Despite three approved therapeutic options, the cross-resistant BCR-ABL(T315I) mutation and compound mutants selected on sequential inhibitor therapy remain major clinical challenges. We report design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants. AP24534 inhibited all tested BCR-ABL mutants in cellular and biochemical assays, suppressed BCR-ABL(T315I)-driven tumor growth in mice, and completely abrogated resistance in cell-based mutagenesis screens. Our work supports clinical evaluation of AP24534 as a pan-BCR-ABL inhibitor for treatment of CML.
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR 97239, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
authors.forename: William C
authors.initials: WC
authors.lastname: Shakespeare
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhu
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.forename: Victor M
authors.initials: VM
authors.lastname: Rivera
authors.forename: Frank
authors.initials: F
authors.lastname: Wang
authors.forename: Lauren T
authors.initials: LT
authors.lastname: Adrian
authors.forename: Tianjun
authors.initials: T
authors.lastname: Zhou
authors.forename: Wei-Sheng
authors.initials: WS
authors.lastname: Huang
authors.forename: Qihong
authors.initials: Q
authors.lastname: Xu
authors.forename: Chester A
authors.initials: CA
authors.lastname: Metcalf
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.forename: Marc M
authors.initials: MM
authors.lastname: Loriaux
authors.forename: Amie S
authors.initials: AS
authors.lastname: Corbin
authors.forename: Scott
authors.initials: S
authors.lastname: Wardwell
authors.forename: Yaoyu
authors.initials: Y
authors.lastname: Ning
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Keats
authors.forename: Yihan
authors.initials: Y
authors.lastname: Wang
authors.forename: Raji
authors.initials: R
authors.lastname: Sundaramoorthi
authors.forename: Mathew
authors.initials: M
authors.lastname: Thomas
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
authors.forename: Joseph
authors.initials: J
authors.lastname: Snodgrass
authors.forename: Lois
authors.initials: L
authors.lastname: Commodore
authors.forename: Tomi K
authors.initials: TK
authors.lastname: Sawyer
authors.forename: David C
authors.initials: DC
authors.lastname: Dalgarno
authors.forename: Michael W N
authors.initials: MW
authors.lastname: Deininger
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Tim
authors.initials: T
authors.lastname: Clackson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545373:ponatinib; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl