The design and preliminary structure–activity relationship studies of benzotriazines as potent inhibitors of Abl and Abl-T315I enzymes
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- 作者：Jianguo Cao ; Richard Fine ; Colleen Gritzen ; John Hood ; Xinshan Kang ; Boris Klebansky ; Dan Lohse ; Chi Ching Mak ; Andrew McPherson ; Glenn Noronha ; Moorthy S.S. Palanki ; Ved P. Pathak ; Joel Renick ; Richa
- 关键词：Abl inhibitor ; Abl-T315I ; Bcr-Abl ; Cancer ; Kinase inhibitor ; Benzotriazines ; CML ; Chronic myeloid leukemia
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2007
- 出版时间：1 November 2007
- 年：2007
- 卷：17
- 期：21
- 页码：5812-5818
- 全文大小：1049 K
文摘
We describe the design, synthesis and structure–activity relationship studies in optimizing a series of benzotriazine compounds as potent inhibitors of both Abl and Abl-T315I enzymes. The design includes targeting of an acid functional residue on the αC-helix that is available only upon kinase activation. This designed interaction provides an advantage in overcoming the challenges arising from the T315I mutation of Abl and transforms poor (ca. 10 μM) inhibitors into those with low nM potency.