title: A type-II kinase inhibitor capable of inhibiting the T315I "gatekeeper" mutant of Bcr-Abl.
abstract: The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I "gatekeeper" mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically relevant Bcr-Abl mutants such as G250E, Q252H, Y253H, E255K, E255V, F317L, and M351T in biochemical and cellular assays. In addition, compound 2 displayed significant in vivo efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. Compound 2 is among the first type-II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design the third generation Bcr-Abl kinase inhibitors.
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Department of Cancer Biology and Department of Biological Chemistry and Molecular Pharmacology, Boston, Massachusetts 02115, USA.
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.forename: Pingda
authors.initials: P
authors.lastname: Ren
authors.forename: Francisco
authors.initials: F
authors.lastname: Adrian
authors.forename: Fangxian
authors.initials: F
authors.lastname: Sun
authors.forename: Hyun Soo
authors.initials: HS
authors.lastname: Lee
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.forename: Guobao
authors.initials: G
authors.lastname: Zhang
authors.forename: Yongping
authors.initials: Y
authors.lastname: Xie
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.forename: Markus
authors.initials: M
authors.lastname: Warmuth
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mestan
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008958:Models, Molecular; D009154:Mutation; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C551935:N-(4-methyl-3-(1-methyl-7-(6-methylpyridin-3-ylamino)-2-oxo-1,2-dihydropyrimido(4,5-d)pyrimidin-3(4H)-yl)phenyl)-3-(trifluoromethyl)benzamide; D011743:Pyrimidines; D011744:Pyrimidinones; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl