title: A coiled-coil mimetic intercepts BCR-ABL1 dimerization in native and kinase-mutant chronic myeloid leukemia.
abstract: Targeted therapy of chronic myeloid leukemia (CML) is currently based on small-molecule inhibitors that directly bind the tyrosine kinase domain of BCR-ABL1. This strategy has generally been successful, but is subject to drug resistance because of point mutations in the kinase domain. Kinase activity requires transactivation of BCR-ABL1 following an oligomerization event, which is mediated by the coiled-coil (CC) domain at the N terminus of the protein. Here, we describe a rationally engineered mutant version of the CC domain, called CC(mut3), which interferes with BCR-ABL1 oligomerization and promotes apoptosis in BCR-ABL1-expressing cells, regardless of kinase domain mutation status. CC(mut3) exhibits strong proapoptotic and antiproliferative activity in cell lines expressing native BCR-ABL1, single kinase domain mutant BCR-ABL1 (E255V and T315I) or compound-mutant BCR-ABL1 (E255V/T315I). Moreover, CC(mut3) inhibits colony formation by primary CML CD34(+) cells ex vivo, including a sample expressing the T315I mutant. These data suggest that targeting BCR-ABL1 with CC mutants may provide a novel alternative strategy for treating patients with resistance to current targeted therapies.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, The University of Utah, Salt Lake City, UT, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Woessner
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Eiring
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, UT, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Bruno
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Zabriskie
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Reynolds
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, UT, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Miller
authors.affiliation: 1] Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA [2] Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT, USA.
authors.forename: T
authors.initials: T
authors.lastname: O'Hare
authors.affiliation: 1] Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA [2] Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Deininger
authors.affiliation: 1] Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA [2] Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, UT, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Lim
mesh_terms: D017209:Apoptosis; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation; D017354:Point Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055503:Protein Multimerization / Q000235:genetics*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl