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

Jun Fan; Yang Dai; Jingwei Shao; Xia Peng; Chen Wang; Sufen Cao; Bin Zhao; Jing Ai; Meiyu Geng; Wenhu Duan

doi:10.1016/j.bmcl.2016.04.028

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. Epub 2016 Apr 12.

Authors

Jun Fan¹, Yang Dai², Jingwei Shao¹, Xia Peng², Chen Wang³, Sufen Cao⁴, Bin Zhao¹, Jing Ai⁵, Meiyu Geng⁶, Wenhu Duan⁷

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aniline Compounds / chemical synthesis
Aniline Compounds / chemistry
Aniline Compounds / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology*
Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Aniline Compounds
Antineoplastic Agents
Protein Kinase Inhibitors
Quinazolines
Receptors, Fibroblast Growth Factor