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Molecules 2018, 23(3), 698; https://doi.org/10.3390/molecules23030698

Structure-Based Discovery of a Series of 5H-Pyrrolo[2,3-b]pyrazine FGFR Kinase Inhibitors

1,2,†
,
3,†
,
4,5,†
,
4,5
,
2
,
5
,
3,* , 5,* , 2,* , 5
,
1,2
and
5,*
1
College of Pharmacy, Nanchang University, 461 Bayi Avenue, Nanchang 330006, China
2
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
3
Drug Design and Discovery Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
4
Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
5
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
These authors contributed equally.
*
Authors to whom correspondence should be addressed.
Received: 2 March 2018 / Revised: 16 March 2018 / Accepted: 17 March 2018 / Published: 19 March 2018
(This article belongs to the Section Medicinal Chemistry)
Full-Text   |   PDF [7554 KB, uploaded 3 May 2018]   |  

Abstract

Fibroblast growth factor receptors (FGFRs), a subfamily of receptor tyrosine kinases, are aberrant in various cancer types, and considered to be promising targets for cancer therapy. We started with a weak-active compound that was identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and optimized it with the guidance of a co-crystal structure of compound 8 with FGFR1. Through rational design, synthesis, and the biological evaluation of a series of 5H-pyrrolo[2,3-b]pyrazine derivatives, we discovered several potent FGFR kinase inhibitors. Among them, compound 13 displayed high selectivity and favorable metabolic properties, demonstrating a promising lead for further development. View Full-Text
Keywords: cancer; FGFR; kinase inhibitor; pyrrolo[2,3-b]pyrazine cancer; FGFR; kinase inhibitor; pyrrolo[2,3-b]pyrazine
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Jiang, A.; Liu, Q.; Wang, R.; Wei, P.; Dai, Y.; Wang, X.; Xu, Y.; Ma, Y.; Ai, J.; Shen, J.; Ding, J.; Xiong, B. Structure-Based Discovery of a Series of 5H-Pyrrolo[2,3-b]pyrazine FGFR Kinase Inhibitors. Molecules 2018, 23, 698.

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