Back to Search
Start Over
Discovery of a series of dimethoxybenzene FGFR inhibitors with 5H-pyrrolo[2,3-b]pyrazine scaffold: structure–activity relationship, crystal structural characterization and in vivo study
- Source :
- Acta Pharmaceutica Sinica. B, Acta Pharmaceutica Sinica B, Vol 9, Iss 2, Pp 351-368 (2019)
- Publication Year :
- 2018
- Publisher :
- Elsevier, 2018.
-
Abstract
- Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors (FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structure—activity relationship was elaborated. Together with in vitro metabolic stability tests and in vivo pharmacokinetic profiling, a representative compound (35) was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor 35 was effective against tumors with FGFR genetic alterations, exhibiting potential for further development.<br />Graphical abstract With the guidance of the crystal structure, we discovered a series of selective FGFR inhibitors bearing 5H-pyrrolo[2,3-b]pyrazine scaffold. After considerable efforts to improve the metabolic stability and pharmacokinetic properties, finally, we obtained a potent and active compound 35 showing in vivo efficacy in xenograft mouse model.fx1
- Subjects :
- Original article
Inhibitor
Structure-based
Fibroblast growth factor
Tyrosine kinase receptor
Receptor tyrosine kinase
03 medical and health sciences
0302 clinical medicine
In vivo
5-Hydrosulfonyl-5H-pyrrolo[2,3-b]pyrazine
Structure–activity relationship
Selectivity
General Pharmacology, Toxicology and Pharmaceutics
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Crystallography
biology
Chemistry
lcsh:RM1-950
In vitro
Hybrid
lcsh:Therapeutics. Pharmacology
Enzyme
Biochemistry
Fibroblast growth factor receptor
030220 oncology & carcinogenesis
biology.protein
Signal transduction
Subjects
Details
- Language :
- English
- ISSN :
- 22113843 and 22113835
- Volume :
- 9
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Acta Pharmaceutica Sinica. B
- Accession number :
- edsair.doi.dedup.....3397f859ac56df71abaab02a4d167d4f