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Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant |
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| Authors: | Thomas Mathew Huang Wei-Sheng Wen David Zhu Xiaotian Wang Yihan Metcalf Chester A Liu Shuangying Chen Ingrid Romero Jan Zou Dong Sundaramoorthi Raji Li Feng Qi Jiwei Cai Lisi Zhou Tianjun Commodore Lois Xu Qihong Keats Jeff Wang Frank Wardwell Scott Ning Yaoyu Snodgrass Joseph T Broudy Marc I Russian Karin Iuliucci John Rivera Victor M Sawyer Tomi K Dalgarno David C Clackson Tim Shakespeare William C |
| Institution: | ARIAD Pharmaceuticals Inc., 26 Lansdowne Street, Cambridge, MA 02139, USA |
| Abstract: | Ponatinib (AP24534) was previously identified as a pan-BCR-ABL inhibitor that potently inhibits the T315I gatekeeper mutant, and has advanced into clinical development for the treatment of refractory or resistant CML. In this study, we explored a novel series of five and six membered monocycles as alternate hinge-binding templates to replace the 6,5-fused imidazopyridazine core of ponatinib. Like ponatinib, these monocycles are tethered to pendant toluanilides via an ethynyl linker. Several compounds in this series displayed excellent in vitro potency against both native BCR-ABL and the T315I mutant. Notably, a subset of inhibitors exhibited desirable PK and were orally active in a mouse model of T315I-driven CML. |
| Keywords: | BCR-ABL inhibitors Gatekeeper mutant Chronic myeloid leukemia Ponatinib Monocycles |
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