化学
药理学
阿布勒
效力
伊马替尼
IC50型
帕纳替尼
酪氨酸激酶
髓系白血病
K562细胞
药代动力学
尼罗替尼
癌症研究
体外
生物化学
受体
生物
作者
Dongfeng Zhang,Peng Li,Yanning Gao,Yaoyao Song,Yaqin Zhu,Hong Su,Baofeng Yang,Li Li,Gang Li,Ningbo Gong,Yang Lü,Huanjie Shao,Chunrong Yu,Huanwei Huang
标识
DOI:10.1021/acs.jmedchem.1c00082
摘要
BCR-ABL kinase inhibition is an effective strategy for the treatment of chronic myeloid leukemia (CML). Herein, we report compound 3a-P1, bearing a difluoro-indene scaffold, as a novel potent pan-inhibitor against BCR-ABL mutants, including the most refractory T315I mutant. As the privileged (S)-isomer compared to its (R)-isomer 3a-P2, 3a-P1 exhibited potent antiproliferative activities against K562 and Ku812 CML cells and BCR-ABL and BCR-ABLT315I BaF3 cells, with IC50 values of 0.4, 0.1, 2.1, and 4.7 nM, respectively. 3a-P1 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, 3a-P1 demonstrated a higher potency than ponatinib in a mice xenograft model of BaF3 harboring BCR-ABLT315I. Overall, the results indicate that 3a-P1 is a promising drug candidate for the treatment of CML to overcome the imatinib-resistant T315I BCR-ABL mutation.
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