2. Academic Validation
  3. Discovery of 4-((N-(2-(dimethylamino)ethyl)acrylamido)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (CHMFL-PDGFR-159) as a highly selective type II PDGFRα kinase inhibitor for PDGFRα driving chronic eosinophilic leukemia

Discovery of 4-((N-(2-(dimethylamino)ethyl)acrylamido)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (CHMFL-PDGFR-159) as a highly selective type II PDGFRα kinase inhibitor for PDGFRα driving chronic eosinophilic leukemia

  • Eur J Med Chem. 2018 Apr 25;150:366-384. doi: 10.1016/j.ejmech.2018.03.003.
Qiang Wang 1,  Feiyang Liu 2,  Shuang Qi 1,  Ziping Qi 1,  Xiao-E Yan 3,  Beilei Wang 2,  Aoli Wang 2,  Wei Wang 1,  Cheng Chen 2,  Xiaochuan Liu 1,  Zongru Jiang 2,  Zhenquan Hu 1,  Li Wang 2,  Wenchao Wang 1,  Tao Ren 4,  Shanchun Zhang 5,  Cai-Hong Yun 6,  Qingsong Liu 7,  Jing Liu 8
Affiliations

Affiliations

  • 1 High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China; CHMFL-HCMTC Target Therapy Joint Laboratory, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China.
  • 2 High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230036, PR China.
  • 3 Institute of Systems Biomedicine, Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
  • 4 Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230088, PR China.
  • 5 CHMFL-HCMTC Target Therapy Joint Laboratory, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China; Hefei Cosource Medicine Technology Co. LTD., 358 Ganquan Road, Hefei, Anhui, 230031, PR China.
  • 6 Institute of Systems Biomedicine, Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China. Electronic address: yunch@hsc.pku.edu.cn.
  • 7 High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China; CHMFL-HCMTC Target Therapy Joint Laboratory, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230036, PR China; Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230088, PR China; Hefei Science Center, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei, 230031, Anhui, PR China. Electronic address: qsliu97@hmfl.ac.cn.
  • 8 High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China; CHMFL-HCMTC Target Therapy Joint Laboratory, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China; Hefei Science Center, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei, 230031, Anhui, PR China. Electronic address: jingliu@hmfl.ac.cn.
PMID: 29544149 DOI: 10.1016/j.ejmech.2018.03.003
Abstract

Through exploration of the non-highly conserved allosteric hydrophobic pocket generated by DFG-out shifting in the inactive conformation, we discovered a highly selective type II PDGFRα kinase inhibitor 15i (CHMFL-PDGFRα-159), which exhibited strong potency against purified PDGFRα (IC50: 132 nM) but not structurally similar PDGFRβ, ABL, c-Kit and VEGFR2/KDR/Flk-1 kinases. In addition, it displayed a high selectivity profile (S score (10) = 0.02) at the concentration of 1 μM among 468 kinases/mutants in the KINOMEscan profiling. X-ray crystal structure of 15i in complex with PDGFRα revealed a distinct binding feature in the allosteric hydrophobic pocket which might help to expand the diversity of type II kinase inhibitors. Compound 15i potently inhibited the proliferation of PDGFRα driving Chronic Eosinophilic Leukemia (CEL) cell line EOL-1 through strong blockage of PDGFRα mediated signaling pathways, arresting cell cycle progression, and induction of Apoptosis. Furthermore, compound 15i effectively suppressed the EOL-1 tumor progression in the xenograft model and increased the survival rate in the engraftment tumor model.

Keywords

CEL; Kinase inhibitor; PDGFR kinase; Type II inhibitor.

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