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, …

WS Huang, CA Metcalf, R Sundaramoorthi…

Index: 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. Journal of Medicinal Chemistry, 2010 , vol. 53, # 12 p. 4701 - 4719

Full Text: HTML

Citation Number: 157

Abstract

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 ...