121st General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Event Hall
Time 4월 19일 (목요일) 11:00~12:30
Code MEDI.P-642
Subject Discovery of Mutant-Selective BCR/ABL-T315I Inhibitors with Reduced Adverse Effects
Authors Yunju Nam, Taebo Sim1,*
KU-KIST, Korea University, Korea
1Chemical Kinomics Research Center, Korea Institute of Science and Technology, Korea
Abstract Chronic myeloid leukemia (CML) has been overcome by the development of imatinib, the small-molecule inhibitor of BCR/ABL kinase. However, resistance to imatinib mainly derived from point mutation in gatekeeper region (T315I) has motivated the development of next generation BCR/ABL inhibitors. Ponatinib is the only clinically approved tyrosine kinase inhibitor that overcomes BCR/ABL-T315I mutant, however it shows cardiotoxic adverse effects such as vascular occlusive events derived from its significant VEGFR2 inhibitory activity. Herein, we report novel 1,6-disubstituted-1H-indole derivatives as highly potent on BCR/ABL-T315I with marginal VEGFR2 inhibition. Among them, pharmacologically optimized compound 6d displayed significant in vivo efficacy in bioluminescent xenograft models using BCR/ABL-T315I Ba/F3 cell lines without notable adverse effects.
E-mail yunjunam33@gmail.com