Discovery of 3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a Potent, Orally Active Pan-Inhibit

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• 作者：Wei-Sheng Huang ; Chester A. Metcalf ; Raji Sundaramoorthi ; Yihan Wang ; Dong Zou ; R. Mathew Thomas ; Xiaotian Zhu ; Lisi Cai ; David Wen ; Shuangying Liu ; Jan Romero ; Jiwei Qi ; Ingrid Chen ; Geetha Banda ; Sc
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：June 24, 2010
• 年：2010
• 卷：53
• 期：12
• 页码：4701-4719
• 全文大小：1386K
• 年卷期：v.53,no.12(June 24, 2010)
• ISSN：1520-4804

文摘

In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon−carbon triple bond linker which skirts the increased bulk of Ile315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC₅₀s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL^T315I expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CML, including patients refractory to all currently approved therapies.