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Design, synthesis and screening studies of potent thiazol-2-amine derivatives as fibroblast growth factor receptor 1
B V S Suneel Kumar, Narasu Lakshmi, M Ravi Kumar
1GVK Biosciences Pvt. Ltd., Phase-1, Technocrats Industrial Estate, Balanagar 500037, Andhra Pradesh, India. Suneelkumar.bvs@gmail.com.
Abstract:
Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in angiogenesis, embryonic development, cell proliferation, cell differentiation, and wound healing. The FGFR isoforms and their receptors (FGFRs) considered as a potential targets and under intense research to design potential anticancer agents. Fibroblast growth factors (FGF's) and its growth factor receptors (FGFR) plays vital role in one of the critical pathway in monitoring angiogenesis. In the current study, quantitative pharmacophore models were generated and validated using known FGFR1 inhibitors. The pharmacophore models were generated using a set of 28 compounds (training). The top pharmacophore model was selected and validated using a set of 126 compounds (test set) and also using external validation. The validated pharmacophore was considered as a virtual screening query to screen a database of 400,000 virtual molecules and pharmacophore model retrieved 2800 hits. The retrieved hits were subsequently filtered based on the fit value. The selected hits were subjected for docking studies to observe the binding modes of the retrieved hits and also to reduce the false positives. One of the potential hits (thiazole-2-amine derivative) was selected based the pharmacophore fit value, dock score, and synthetic feasibility. A few analogues of the thiazole-2-amine derivative were synthesized. These compounds were screened for FGFR1 activity and anti-proliferative studies. The top active compound showed 56.87% inhibition of FGFR1 activity at 50 µM and also showed good cellular activity. Further optimization of thiazole-2-amine derivatives is in progress.
Insights
Researchers developed a pharmacophore model to identify new FGFR1 inhibitors for cancer therapy. A promising thiazole-2-amine derivative was synthesized and showed significant FGFR1 inhibition and anti-proliferative effects.
Area of Science:
- Medicinal Chemistry
- Computational Drug Design
- Oncology
Background:
- Fibroblast growth factor receptor 1 (FGFR1) is crucial for angiogenesis and cell development, making it a target for anticancer drug discovery.
- FGFR1's role in angiogenesis and cell proliferation highlights its significance in cancer progression.
Purpose of the Study:
- To generate and validate quantitative pharmacophore models for identifying novel FGFR1 inhibitors.
- To virtually screen a large compound library and identify potential drug candidates targeting FGFR1.
Main Methods:
- Quantitative pharmacophore models were built using known FGFR1 inhibitors and validated rigorously.
- A virtual screening of 400,000 molecules was performed, followed by hit filtering based on fit value and docking studies.
- Hit compounds were further evaluated for FGFR1 inhibitory and anti-proliferative activities.
Main Results:
- A validated pharmacophore model successfully identified 2800 potential hits from a virtual library.
- A thiazole-2-amine derivative demonstrated significant FGFR1 inhibition (56.87% at 50 µM) and cellular activity.
- Synthesized analogues showed promising FGFR1 inhibitory and anti-proliferative effects.
Conclusions:
- The study successfully identified and validated a pharmacophore model for FGFR1 inhibitor discovery.
- A novel thiazole-2-amine derivative shows potential as an anticancer agent targeting FGFR1.
- Further optimization of these derivatives is warranted for developing effective cancer therapeutics.
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