Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML).
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.
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China.
Feiyang
F
Liu
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui, 230031, P. R. China.
Beilei
B
Wang
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui, 230031, P. R. China.
Qiang
Q
Wang
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui, 230031, P. R. China.
Ziping
Z
Qi
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui, 230031, P. R. China.
Cheng
C
Chen
Institute of Systems Biomedicine, Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China.
Lu-Lu
LL
Kong
Institute of Systems Biomedicine, Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China.
Ji-Yun
JY
Chen
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|Department of Chemistry, University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China.
Xiaochuan
X
Liu
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China.
Aoli
A
Wang
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China.
Chen
C
Hu
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui, 230031, P. R. China.
Wenchao
W
Wang
Department of Hematology, The Second Hospital of Anhui Medical University, Hefei, Anhui, 230601, P. R. China.|Hematology Research Center, Anhui Medical University, Hefei, Anhui 230601, P. R. China.
Huiping
H
Wang
Department of Hematology, The Second Hospital of Anhui Medical University, Hefei, Anhui, 230601, P. R. China.|Hematology Research Center, Anhui Medical University, Hefei, Anhui 230601, P. R. China.
Fan
F
Wu
Department of Hematology, The Second Hospital of Anhui Medical University, Hefei, Anhui, 230601, P. R. China.|Hematology Research Center, Anhui Medical University, Hefei, Anhui 230601, P. R. China.
Yanjie
Y
Ruan
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui, 230031, P. R. China.
Shuang
S
Qi
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China.
Juan
J
Liu
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui, 230031, P. R. China.
Fengming
F
Zou
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui, 230031, P. R. China.
Zhenquan
Z
Hu
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui, 230031, P. R. China.
Wei
W
Wang
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui, 230031, P. R. China.
Li
L
Wang
CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui, 230031, P. R. China.|Hefei Cosource Medicine Technology Co. Ltd., Hefei, 230031, Anhui, P. R. China.
Shanchun
S
Zhang
Institute of Systems Biomedicine, Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China.
Cai-Hong
CH
Yun
Department of Hematology, The Second Hospital of Anhui Medical University, Hefei, Anhui, 230601, P. R. China.|Hematology Research Center, Anhui Medical University, Hefei, Anhui 230601, P. R. China.
Zhimin
Z
Zhai
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui, 230031, P. R. China.
Jing
J
Liu
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui, 230031, P. R. China.
Qingsong
Q
Liu
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D016044:Fusion Proteins, bcr-abl
BCR-ABL; Chronic Myeloid Leukemia; PDGFR; kinase inhibitor