2. Academic Validation
  3. Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant

Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant

  • Bioorg Med Chem Lett. 2011 Jun 15;21(12):3743-8. doi: 10.1016/j.bmcl.2011.04.060.
Mathew Thomas 1,  Wei-Sheng Huang,  David Wen,  Xiaotian Zhu,  Yihan Wang,  Chester A Metcalf,  Shuangying Liu,  Ingrid Chen,  Jan Romero,  Dong Zou,  Raji Sundaramoorthi,  Feng Li,  Jiwei Qi,  Lisi Cai,  Tianjun Zhou,  Lois Commodore,  Qihong Xu,  Jeff Keats,  Frank Wang,  Scott Wardwell,  Yaoyu Ning,  Joseph T Snodgrass,  Marc I Broudy,  Karin Russian,  John Iuliucci,  Victor M Rivera,  Tomi K Sawyer,  David C Dalgarno,  Tim Clackson,  William C Shakespeare
Affiliations

Affiliation

  • 1 ARIAD Pharmaceuticals Inc., 26 Lansdowne Street, Cambridge, MA 02139, USA. [email protected]
PMID: 21561767 DOI: 10.1016/j.bmcl.2011.04.060
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.

Figures