Discovery of a highly potent kinase inhibitor capable of overcoming multiple imatinib-resistant ABL mutants for chronic myeloid leukemia (CML)

• Published in: European journal of pharmacology 2021-04, Vol.897, p.173944-173944, Article 173944
• Main Authors: Lu, Tingting, Cao, Jiangyan, Zou, Fengming, Li, Xixiang, Wang, Aoli, Wang, Wenliang, Liang, Huamin, Liu, Qingwang, Hu, Chen, Chen, Cheng, Hu, Zhenquan, Wang, Wenchao, Li, Lili, Ge, Jian, Shen, Yang, Ren, Tao, Liu, Jing, Xia, Ruixiang, Liu, Qingsong
• Format: Article
• Language: English
• Subjects: ABL mutants; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; BCR-ABL; Cell Proliferation - drug effects; Chronic myeloid leukemia; Drug Resistance, Neoplasm - drug effects; Female; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Gene Fusion; Humans; Imatinib Mesylate - pharmacology; Imatinib resistance; K562 Cells; Kinase inhibitor; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Mice; Mice, Nude; Mutation; Protein Kinase Inhibitors - pharmacology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2021.173944

As the critical driving force for chronic myeloid leukemia (CML), BCR gene fused ABL kinase has been extensively explored as a validated target of drug discovery. Although imatinib has achieved tremendous success as the first-line treatment for CML, the long-term application ultimately leads to resistance, primarily via various acquired mutations occurring in the BCR-ABL kinase. Although dasatinib and nilotinib have been approved as second-line therapies that could overcome some of these mutants, the most prevalent gatekeeper T315I mutant remains unconquered. Here, we report a novel type II kinase inhibitor, CHMFL-48, that potently inhibits the wild-type BCR-ABL (wt) kinase as well as a panel of imatinib-resistant mutants, including T315I, F317L, E255K, Y253F, and M351T. CHMFL-48 displayed great inhibitory activity against ABL wt (IC50: 1 nM, 70-fold better than imatinib) and the ABL T315I mutant (IC50: 0.8 nM, over 10,000-fold better than imatinib) in a biochemical assay and potently blocked the autophosphorylation of BCR-ABL wt and BCR-ABL mutants in a cellular context, which further affected downstream signalling mediators, including signal transducer and activator of transcription 5 (STAT5) and CRK like proto-oncogene (CRKL), and led to the cell cycle progression blockage as well as apoptosis induction. CHMFL-48 also exhibited great anti-leukemic efficacies in vivo in K562 cells and p210-T315I-transformed BaF3 cell-inoculated murine models. This discovery extended the pharmacological diversity of BCR-ABL kinase inhibitors and provided more potential options for anti-CML therapies. [Display omitted] •CHMFL-48 is sensitive to ABL gatekeeper T315I mutant.•CHMFL-48 inhibits ABL wt kinase as well as a panel of imatinib resistant mutants.•CHMFL-48 exhibits great anti-leukemic efficacies in vivo.•CHMFL-48 inhibits the growth of human CML patient-derived primary cells.