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Cancer Biol Ther. 2019;20(6):877-885. doi: 10.1080/15384047.2019.1579958. Epub 2019 Mar 20.

Discovery and characterization of a novel highly potent and selective type II native and drug-resistant V299L mutant BCR-ABL inhibitor (CHMFL-ABL-039) for Chronic Myeloid Leukemia (CML).

Wu J1,2, Wang A1, Li X1,3, Chen C1,2, Qi Z1,3, Hu C1,2, Wang W1,2, Wu H1, Huang T4, Zhao M4, Wang W1,3, Hu Z1, Liu Q4, Wang B1,2, Wang L1,2, Li L5, Ge J5, Ren T4, Xia R5, Liu J1,3, Liu Q1,2,3,4.

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a High Magnetic Field Laboratory , Chinese Academy of Sciences , Hefei , Anhui , P. R. China.
b University of Science and Technology of China , Hefei , Anhui , P. R. China.
c CHMFL-HCMTC Target Therapy Joint Laboratory , Hefei , Anhui , P. R. China.
d Precision Targeted Therapy Discovery Center, Institute of Technology Innovation , Hefei Institutes of Physical Science, Chinese Academy of Sciences , Hefei , Anhui , P. R. China.
e Department of Hematology , the First Hospital of Anhui Medical University , Hefei , Anhui , P.R. China.


BCR fused ABL kinase is the critical driving oncogene for chronic myeloid leukemia (CML) and has been extensively studied as the drug discovery target in the past decade. The successful introduction of tyrosine kinase inhibitors (TKI) such as Imatinib, Dasatinib and Bosutinib has greatly improved the CML patient survival rate. However, upon the chronic treatment, a variety of TKI resistant mutants, such as the V299L mutant which has been found in more and more patients with the high-throughput sequencing technology, are observed, although the incidence is still considered rare compared to the more prevalent gatekeeper T315I mutant. However, with the progress of the precision medicine concept, the rare mutation (or the orphan drug target) has attracted more and more attention. Here we report a novel type II BCR-ABL kinase inhibitor, CHMFL-ABL-039, which not only displayed great potency (IC50: 7.9 nM) and selectivity (S score (1) = 0.02) against native ABL kinase among other kinases in the kinome, but also exhibited great potency (IC50: 27.9 nM) and selectivity against Imatinib-resistant V299L mutant among other frequently observed ABL kinase mutants. CHMFL-ABL-039 has demonstrated greater efficacies than Imatinib regarding to the anti-proliferation, inhibition of the signaling pathway, arrest of cell cycle progression, induction of apoptosis in vitro and suppression of the tumor progression in vivo in the native and V299L mutated BCR-ABL kinase-driven cells/xenograft models. It would be a useful pharmacological tool to study the TKI resistant ABL V299L mutant-mediated pathology and provide a potential precise treatment approach for this orphan CML subtype in the precision medicine era.


BCR-ABL; PDGFR; chronic myeloid leukemia; kinase inhibitor

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