Discovery of a Candidate Containing an (S)-3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden Scaffold as a Highly Potent Pan-Inhibitor of the BCR-ABL Kinase Including the T315I-Resistant Mutant for the Treatment of Chronic Myeloid Leukemia

Abstract

BCR-ABL kinase inhibition is an effective strategy for the treatment of chronic myeloid leukemia (CML). Herein, we report compound <b>3a-P1</b>, bearing a difluoro-indene scaffold, as a novel potent pan-inhibitor against BCR-ABL mutants, including the most refractory T315I mutant. As the privileged (<i>S</i>)-isomer compared to its (<i>R</i>)-isomer <b>3a-P2</b>, <b>3a-P1</b> exhibited potent antiproliferative activities against K562 and Ku812 CML cells and BCR-ABL and BCR-ABL^T315I BaF3 cells, with IC₅₀ values of 0.4, 0.1, 2.1, and 4.7 nM, respectively. <b>3a-P1</b> displayed a good safety profile in a battery of assays, including single-dose toxicity, hERG K⁺, and genotoxicity. It also showed favorable mice pharmacokinetic properties with a good oral bioavailability (32%), a reasonable half-life (4.61 h), and a high exposure (1386 h·ng/mL). Importantly, <b>3a-P1</b> demonstrated a higher potency than ponatinib in a mice xenograft model of BaF3 harboring BCR-ABL^T315I. Overall, the results indicate that <b>3a-P1</b> is a promising drug candidate for the treatment of CML to overcome the imatinib-resistant T315I BCR-ABL mutation.