Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML)
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Feiyang Liu1,2,*, Beilei Wang1,3,*, Qiang Wang1,3,*, Ziping Qi1,3,*, Cheng Chen1,3,*, Lu-Lu Kong4,*, Ji-Yun Chen4, Xiaochuan Liu1,5, Aoli Wang1,2, Chen Hu1,2, Wenchao Wang1,3, Huiping Wang6,7, Fan Wu6,7, Yanjie Ruan6,7, Shuang Qi1,3, Juan Liu1,2, Fengming Zou1,3, Zhenquan Hu1,3, Wei Wang1,3, Li Wang1,3, Shanchun Zhang3,8, Cai-Hong Yun4, Zhimin Zhai6,7, Jing Liu1,3, Qingsong Liu1,2,3
1High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China
2University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China
3CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui, 230031, P. R. China
4Institute of Systems Biomedicine, Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China
5Department of Chemistry, University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China
6Department of Hematology, The Second Hospital of Anhui Medical University, Hefei, Anhui, 230601, P. R. China
7Hematology Research Center, Anhui Medical University, Hefei, Anhui 230601, P. R. China
8Hefei Cosource Medicine Technology Co. Ltd., Hefei, Anhui, 230031, P. R. China
* These authors contribute equally to this work
Cai-Hong Yun, email: [email protected]
Zhimin Zhai, email: [email protected]
Jing Liu, email: [email protected]
Qingsong Liu, email: [email protected]
Keywords: BCR-ABL, PDGFR, Chronic Myeloid Leukemia, kinase inhibitor
Received: February 06, 2016 Accepted: June 01, 2016 Published: June 14, 2016
BCR gene fused ABL kinase is the critical driving force for the Philadelphia Chromosome positive (Ph+) Chronic Myeloid Leukemia (CML) and has been extensively explored as a drug target. With a structure-based drug design approach we have discovered a novel inhibitor CHMFL-074, that potently inhibits both the native and a variety of clinically emerged mutants of BCR-ABL kinase. The X-ray crystal structure of CHMFL-074 in complex with ABL1 kinase (PDB ID: 5HU9) revealed a typical type II binding mode (DFG-out) but relatively rare hinge binding. Kinome wide selectivity profiling demonstrated that CHMFL-074 bore a high selectivity (S score(1) = 0.03) and potently inhibited ABL1 kinase (IC50: 24 nM) and PDGFR α/β (IC50: 71 nM and 88 nM). CHMFL-074 displayed strong anti-proliferative efficacy against BCR-ABL–driven CML cell lines such as K562 (GI50: 56 nM), MEG-01 (GI50: 18 nM) and KU812 (GI50: 57 nM). CHMFL-074 arrested cell cycle into the G0/G1 phase and induced apoptosis in the Ph+ CML cell lines. In addition, it potently inhibited the CML patient primary cell’s proliferation but did not affect the normal bone marrow cells. In the CML cell K562 inoculated xenograft mouse model, oral administration of 100 mg/kg/d of CHMFL-074 achieved a tumor growth inhibition (TGI) of 65% without exhibiting apparent toxicity. As a potential drug candidate for fighting CML, CHMFL-074 is under extensive preclinical safety evaluation now.
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