2. Academic Validation
  3. Design, synthesis and biological evaluation of pyrazolylaminoquinazoline derivatives as highly potent pan-fibroblast growth factor receptor inhibitors

Design, synthesis and biological evaluation of pyrazolylaminoquinazoline derivatives as highly potent pan-fibroblast growth factor receptor inhibitors

  • Bioorg Med Chem Lett. 2016 Jun 1;26(11):2594-9. doi: 10.1016/j.bmcl.2016.04.028.
Jun Fan 1,  Yang Dai 2,  Jingwei Shao 1,  Xia Peng 2,  Chen Wang 3,  Sufen Cao 4,  Bin Zhao 1,  Jing Ai 5,  Meiyu Geng 6,  Wenhu Duan 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 2 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 3 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 4 School of Pharmacy, East China University of Science & Technology, 130 Mei Long Road, Shanghai 200237, China.
  • 5 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: jai@simm.ac.cn.
  • 6 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: mygeng@simm.ac.cn.
  • 7 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: whduan@simm.ac.cn.
PMID: 27117427 DOI: 10.1016/j.bmcl.2016.04.028
Abstract

Fibroblast Growth Factor receptors (FGFRs) are important oncology targets due to the dysregulation of this signaling pathway in a wide variety of human cancers. We identified a series of pyrazolylaminoquinazoline derivatives as potent FGFR inhibitors with low nanomolar potency. The representative compound 29 strongly inhibited FGFR1-3 kinase activity and suppressed FGFR signaling transduction in FGFR-addicted Cancer cells; FGFRs-driven cell proliferation was also strongly inhibited regardless of mechanistic complexity implicated in FGFR activation, which further confirmed that 29 was a potent pan-FGFR inhibitor. The flexibility of our structure offered the potential to preserve good affinity for mutant FGFR, which is important for developing TKIs with long-term efficacy.

Keywords

Antitumor; FGFR inhibitor; Pyrazolylaminoquinazoline.

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