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FGFR1 Inhibitors

We have identified six classes of ATP-competitive small-molecular inhibitors of protein kinase FGFR1 (fibroblast growth factor receptor 1) using computer-based rational design approach.

FGFR1 is transmembrane protein which belong to the family of receptor tyrosine kinases (RTK). FGFR's ligand is fibroblast growth factor (FGF), group of small protein. FGF binding results in receptor dimerization and kinase domain activation with consequent autophosphorylation tyrosine residues in FGFR1. Phosphorylated tyrosine residues act as docking sites for adaptor proteins leading to activation of multiple signal transduction pathways (RAS-RAF–MEK– ERK1/2, PI3K–PKB and PLC-γ/РКС). FGFR1 activation initiates cell proliferation, differentiation, migration, angiogenesis and survival.

FGFR1 scheme


FGFR1 play a critical role in formation of mesoderm and organogenesis of the nervous system, the mammary gland, the lungs in embryogenesis. In the adult, FGFR regulate tissue homeostasis, tissue repair, angiogenesis, inflammation, and adipocytes differentiation. Point mutations, gene amplification or overexpression of FGFR1 have been described in several oncological diseases such as lung cancer, glioma, breast cancer, prostate cancer, lymphoma, melanoma and others. Other FGFR kinases also plays role in development of cancers such as bladder cancer, myeloma, sarcoma, gastric cancer and cervical cancer.

FGFR1 inhibitors can be implemented for treatment of cancers with FGFR1 altered activity. FGFR1 inhibitors have revealed high efficiency in experiments in vitro and in in vivo in various types of tumors with increased activity of this kinase. Currently have been founded several classes of inhibitors of FGFR1, many of them are under clinical trials.

Our search of inhibitors of FGFR1 started from receptor-based virtual screening of our department chemical compounds collection. To increase the percentage found inhibitors we used verification protocol of screening and fine-tuning the parameters on set FGFR1 inhibitors with known position in the binding site. As a result, we have 32 classes of inhibitors with IC50 less than 20 µM, representing 6% of the total number of tested compounds. For the most promising classes of inhibitors was made searching and testing analogues from the collection of chemical compounds. The most active classes of compounds were optimized by direct chemical synthesis and tested on antiproliferative activity in collaboration with the department of human genetics. Below are inhibitors of the published data:

N-phenylnaphthostyril-1-sulfonamides

fgfr1_im4_new1New class of FGFR1 kinase inhibitors with naphthostyril heterocycle has been identified. A series of N-phenylnaphthostyril-1-sulfonamides has been synthesized and tested in vitro. It was...

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N-phenylthieno[2,3-d]pyrimidin-4-amines

fgfr1 im1Thienopyrimidine derivatives have attracted great interest as protein kinase inhibitors over the past years. They were found to be active against VEGFR, EGFR, Aurora kinase, Tie-2, Tpl2...

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Quinazolines

Figure 1. Quinazoline inhibitor of FGFR1.Quinazolines is another known class of RTK inhibitors that is widely represented in the department chemical collection. We investigated the relationship between the substituents at...

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Oxindoles

Figure 1. Oxindole inhibitor of FGFR1.Oxindoles are known class of inhibitors of RTK, including FGFR1. We perform searching of FGFR1 inhibitors among available in department collection oxindole compounds. The result has found...

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Phenylbenzisoxazoles and aminopyrimidines

Figure 1. Phenylbenzisoxazole and aminopyrimidine inhibitors of FGFR1.Phenylbenzisoxazoles and aminopyrimidines were also found from virtual screening. Search for analogues of these inhibitors reveal the most active compounds with an IC50 of 5 and...

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Flavones

Figure 1. The binding mode of flavone inhibitor of FGFR1 in the ATP-binding site. Hydrogen bonds are shown by the dashed lines.One of the first discovered in the screening of inhibitors of FGFR1 classes are flavones. These compounds belong to a class of chromones which are widely represented in nature. They and...

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Other kinase inhibitors research:

ASK1 Inhibitors
Identification of 3H-naphtho[1,2,3-de]quinoline-2,7-diones as Inhibitors of ASK1 Image
Virtual screening and biochemical screening allowed us to identify...



 

CK2 Inhibitors
4'-hydroxyflavones Image
The novel synthetic flavone inhibitors (4'-hydroxyflavones) were identified...



 

FGFR1 Inhibitors
N-phenylthieno[2,3-d]pyrimidin-4-amines Image
Thienopyrimidine derivatives have attracted great interest as protein kinase...



 

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