The fibroblast growth factor receptor 1 (FGFR1), tyrosine kinase receptor, plays an important role in angiogenesis, embryonic development, cell proliferation, cell differentiation and wound healing.
The FGFR isoforms and their receptors (FGFRs) are considered as an important drug targets for anticancer therapy. Amplification of FGFR1 is one of the key genetic alterations in squamous cell lung carcinoma and hormone receptor-positive breast cancer [1-2]. Currently, several FGFR-selective inhibitors are under clinical trials, targeting patients who have FGFR genetic alterations. These inhibitors often share a common structural motifs that are also present in inhibitors of other members of the receptor tyrosine kinase (RTK) family. Thus, it is possible that a common single mutation would confer resistance to these inhibitors. A potential strategy to mitigate this issue is to find a novel inhibitor with a different chemical scaffold.
Life Chemicals has created its library of potential of FGFR1 kinase inhibitors, based on a diversity set of drug-like compounds from the Life Chemicals Stock Screening Collection using receptor- based approach. Initially, we filtered our compounds through medicinal chemistry filters that include PAINS & toxicophore filters and the Rule of Five restrictions. Thereafter, we analyzed known X-Ray structures of human FGFR1 kinase and selected a protein-inhibitor complex from 3RHXPDB entry (with inactive conformation of the kinase) for in silico screening. The Unity Query Model (UNITY Tool, SYBYL-X) of protein binding site was created based on the features of identified key amino acids: Ala564, Glu571, Tyr563, Leu484, Phe489, Asp641, Leu630, Ile545, Phe642, Glu531, Val492, Glu562, Met535. Screening was launched with the Unity Flex-Search tool for the database of prepared ligands from the pre-selected 50,000 diversity set from the Life Chemicals Stock Collection. Retrieved hits were filtered on the basis of the QFit value. Selected compounds were subsequently docked with Surflex-Dock to identify binding modes of the hits and to reduce false positives (Fig.1).
The total number of compounds in the library is 646.
Fig. 1. An example of the binding mode of the ligand (F1860-0430) from the Life Chemicals FGFR1 Kinase Targeted Library
- Comprehensive genomic characterization of squamous cell lung cancers. Nature, 2012, 489, pp. 519–25.
- Turner N., Pearson A. et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res., 2010, 70, pp. 2085–94.
- Eathiraj S., Palma R.A. Novel mode of protein kinase inhibition exploiting hydrophobic motifs of autoinhibited ki- nases: discovery of ATP-independent inhibitors of fibroblast growth factor receptor. J. Biol. Chem., 2011, 286, pp. 20677-20687.