A type-II kinase inhibitor capable of inhibiting the T315I "gatekeeper" mutant of Bcr-Abl.
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.
Choi
Hwan Geun
HG
Dana Farber Cancer Institute, Harvard Medical School, Department of Cancer Biology and Department of Biological Chemistry and Molecular Pharmacology, Boston, Massachusetts 02115, USA.
Ren
Pingda
P
Adrian
Francisco
F
Sun
Fangxian
F
Lee
Hyun Soo
HS
Wang
Xia
X
Ding
Qiang
Q
Zhang
Guobao
G
Xie
Yongping
Y
Zhang
Jianming
J
Liu
Yi
Y
Tuntland
Tove
T
Warmuth
Markus
M
Manley
Paul W
PW
Mestan
Jürgen
J
Gray
Nathanael S
NS
Sim
Taebo
T
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
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