2. Academic Validation
  3. A type-II kinase inhibitor capable of inhibiting the T315I "gatekeeper" mutant of Bcr-Abl

A type-II kinase inhibitor capable of inhibiting the T315I "gatekeeper" mutant of Bcr-Abl

  • J Med Chem. 2010 Aug 12;53(15):5439-48. doi: 10.1021/jm901808w.
Hwan Geun Choi 1,  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
Affiliations

Affiliation

  • 1 Dana Farber Cancer Institute, Harvard Medical School, Department of Cancer Biology and Department of Biological Chemistry and Molecular Pharmacology, Boston, Massachusetts 02115, USA.
PMID: 20604564 DOI: 10.1021/jm901808w
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-10943
    98.08%, BCR-ABL 抑制剂
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