Abstract
Abnormality of fibroblast growth factor receptor (FGFR)-mediated signaling pathways were frequently found in various human malignancies, making FGFRs hot targets for cancer treatment. To address the consistent need for a new chemotype of FGFR inhibitors, here, we started with a hit structure identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and conducted a chemical optimization. After exploring three parts of the hit compound, we finally discovered a new series of pyrrolo[2,3-b]pyrazine FGFR inhibitors, which contain a novel scaffold and unique molecular shape. We believe that our findings can help others to further develop selective FGFR inhibitors.
Highlights
In the human genome, a total of 22 fibroblast growth factors (FGFs) have been identified, and there are four fibroblast growth factor receptors (FGFRs) that respond to and mediate the signaling from fibroblast growth factors [1,2,3,4]
fibroblast growth factor receptor 1 (FGFR1) ATP binding site prepared from a PDB (Protein Data Bank) structure (PDB code: 3TT0) [16]
The benzene group the hinge binder to anchor the molecule in the ATP binding site of FGFR1
Summary
A total of 22 fibroblast growth factors (FGFs) have been identified, and there are four fibroblast growth factor receptors (FGFRs) that respond to and mediate the signaling from fibroblast growth factors [1,2,3,4]. Increasing evidence highlights the importance of FGFR signaling pathways in the regulation of several basic biologic processes, including tissue development, angiogenesis, and tissue regeneration [5,6]. Abnormal signaling involving FGFRs has been frequently found in various human malignancies, making FGFRs hot targets in anticancer drug development [7,8,9]. Aberrant FGFR signaling could be caused by different mechanisms, including activating mutations in FGFRs, oncogenic fusion of FGFRs and over-expression of FGFRs [10]. As investigated by Patani et al [14], due to the landscape of activated mutations in FGFR kinases, the above-mentioned FGFR inhibitors (1, 2, 3) exhibited distinct
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