A type-ii kinase inhibitor capable of inhibiting the T315I "Gatekeeper" mutant of Bcr-Abl

Hwan Geun Choi, Pingda Ren, Francisco Adrian, Fangxian Sun, Hyun Soo Lee, Xia Wang, Qiang Ding, Guobao Zhang, Yongping Xie, Jianming Zhang, Yi Liu, Tove Tuntland, Markus Warmuth, Paul W. Manley, Jürgen Mestan, Nathanael S. Gray, Taebo Sim

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)5439-5448
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number15
Publication statusPublished - 2010 Aug 12

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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