Journal of medicinal chemistry · 2010
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-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant.
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Huang Wei-Sheng, Metcalf Chester A, Sundaramoorthi Raji, Wang Yihan, Zou Dong, Thomas R Mathew, Zhu Xiaotian, Cai Lisi, Wen David, Liu Shuangying, Romero Jan, Qi Jiwei, Chen Ingrid, Banda Geetha, Lentini Scott P, Das Sasmita, Xu Qihong, Keats Jeff, Wang Frank, Wardwell Scott, Ning Yaoyu, Snodgrass Joseph T, Broudy Marc I, Russian Karin, Zhou Tianjun, Commodore Lois, Narasimhan Narayana I, Mohemmad Qurish K, Iuliucci John, Rivera Victor M, Dalgarno David C, Sawyer Tomi K, Clackson Tim, Shakespeare William C
Аннотация
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 IC(50)s, 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.