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
  • 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.

Products