2. Academic Validation
  3. Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia

Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia

  • J Med Chem. 2016 Mar 10;59(5):1984-2004. doi: 10.1021/acs.jmedchem.5b01618.
Xiaofei Liang 1 2,  Xiaochuan Liu 1 3,  Beilei Wang 1 2,  Fengming Zou 1 2,  Aoli Wang 1 4,  Shuang Qi 1 2,  Cheng Chen 1 2,  Zheng Zhao 1 2,  Wenchao Wang 1 2,  Ziping Qi 1 2,  Fengchao Lv 1 4,  Zhenquan Hu 1 2,  Li Wang 1 2,  Shanchun Zhang 2 5,  Qingsong Liu 1 2 4 6,  Jing Liu 1 2
Affiliations

Affiliations

  • 1 High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
  • 2 CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
  • 3 Department of Chemistry, University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
  • 4 University of Science and Technology of China, P. R. China , Anhui Hefei 230036, P. R. China.
  • 5 Hefei Cosource Medicine Technology Co. LTD. , 358 Ganquan Road, Hefei, Anhui 230031, P. R. China.
  • 6 Hefei Science Center, Chinese Academy of Sciences , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
PMID: 26789553 DOI: 10.1021/acs.jmedchem.5b01618
Abstract

Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) Bcr-Abl Inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-Kit kinase, which is the common target of currently clinically used Bcr-Abl inhibitors. Through significant suppression of the Bcr-Abl autophosphorylation (EC50 about 100 nM) and downstream mediators such as STAT5, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI50 = 14 nM), KU812 (GI50 = 25 nM), and MEG-01 (GI50 = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.

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