title: Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors.
abstract: In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Department of Cancer Biology, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA.
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Adrián
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jahnke
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Cowan-Jacob
authors.forename: Allen G
authors.initials: AG
authors.lastname: Li
authors.forename: Roxana E
authors.initials: RE
authors.lastname: Iacob
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.forename: John
authors.initials: J
authors.lastname: Powers
authors.forename: Christine
authors.initials: C
authors.lastname: Dierks
authors.forename: Fangxian
authors.initials: F
authors.lastname: Sun
authors.forename: Gui-Rong
authors.initials: GR
authors.lastname: Guo
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.forename: Barun
authors.initials: B
authors.lastname: Okram
authors.forename: Yongmun
authors.initials: Y
authors.lastname: Choi
authors.forename: Amy
authors.initials: A
authors.lastname: Wojciechowski
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.forename: Guoxun
authors.initials: G
authors.lastname: Liu
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fendrich
authors.forename: André
authors.initials: A
authors.lastname: Strauss
authors.forename: Navratna
authors.initials: N
authors.lastname: Vajpai
authors.forename: Stephan
authors.initials: S
authors.lastname: Grzesiek
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Badry
authors.initials: B
authors.lastname: Bursulaya
authors.forename: Mohammad
authors.initials: M
authors.lastname: Azam
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: John R
authors.initials: JR
authors.lastname: Engen
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.forename: Markus
authors.initials: M
authors.lastname: Warmuth
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D001665:Binding Sites; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D003460:Crystallization; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C508526:GNF-2 compound; D010879:Piperazines; D011743:Pyrimidines; C406060:abl-bcr fusion protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib