Research Papers:

Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML)

Feiyang Liu, Beilei Wang, Qiang Wang, Ziping Qi, Cheng Chen, Lu-Lu Kong, Ji-Yun Chen, Xiaochuan Liu, Aoli Wang, Chen Hu, Wenchao Wang, Huiping Wang, Fan Wu, Yanjie Ruan, Shuang Qi, Juan Liu, Fengming Zou, Zhenquan Hu, Wei Wang, Li Wang, Shanchun Zhang, Cai-Hong Yun, Zhimin Zhai, Jing Liu and Qingsong Liu _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:45562-45574. https://doi.org/10.18632/oncotarget.10037

Metrics: PDF 2653 views  |   HTML 3032 views  |   ?  


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

Correspondence to:

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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 10037