title: Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036.
abstract: Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for patients with chronic myeloid leukemia (CML). Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead "switch-control" inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1(T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph(+) leukemia.
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Chan
authors.forename: Scott C
authors.initials: SC
authors.lastname: Wise
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kaufman
authors.forename: Yu Mi
authors.initials: YM
authors.lastname: Ahn
authors.forename: Carol L
authors.initials: CL
authors.lastname: Ensinger
authors.forename: Torsten
authors.initials: T
authors.lastname: Haack
authors.forename: Molly M
authors.initials: MM
authors.lastname: Hood
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jones
authors.forename: John W
authors.initials: JW
authors.lastname: Lord
authors.forename: Wei Ping
authors.initials: WP
authors.lastname: Lu
authors.forename: David
authors.initials: D
authors.lastname: Miller
authors.forename: William C
authors.initials: WC
authors.lastname: Patt
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Smith
authors.forename: Peter A
authors.initials: PA
authors.lastname: Petillo
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rutkoski
authors.forename: Hanumaiah
authors.initials: H
authors.lastname: Telikepalli
authors.forename: Lakshminarayana
authors.initials: L
authors.lastname: Vogeti
authors.forename: Tony
authors.initials: T
authors.lastname: Yao
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chun
authors.forename: Robin
authors.initials: R
authors.lastname: Clark
authors.forename: Peter
authors.initials: P
authors.lastname: Evangelista
authors.forename: L Cristina
authors.initials: LC
authors.lastname: Gavrilescu
authors.forename: Katherine
authors.initials: K
authors.lastname: Lazarides
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Zaleskas
authors.forename: Lance J
authors.initials: LJ
authors.lastname: Stewart
authors.forename: Richard A
authors.initials: RA
authors.lastname: Van Etten
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Flynn
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl