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Published on: September 30, 2019
Thalidomide and Its Analogs Differentially Target Fibroblast Growth Factor Receptors: Thalidomide Suppresses FGFR
Abstract:
Thalidomide is an infamous teratogen and it is continuously being explored for its anticancer properties. Fibroblast growth factor receptors (FGFRs) are implicated in embryo development and cancer pathophysiology. With striking similarities observed between FGFR implicated conditions and thalidomide embryopathy, we hypothesized thalidomide targets FGFRs. We utilized three different cell lines and chicken embryo model to investigate the effects of thalidomide and analogs on FGFR expression. We performed molecular docking, KINOMEscan analysis, and kinase activity assays to study the drug-protein interactions. The expression of FGFR1 and FGFR2 was differentially regulated by all the three drugs in cells as well as in developing organs. Transcriptome analysis of thalidomide-treated chick embryo strongly suggests the modulation of FGFR signaling and key transcription factors. Corroboration with previous studies suggests that thalidomide might affect FGFR expression through the transcription factor, E2F1. At the protein level, molecular docking predicted all three analogs to interact with lysine residue at 517th and 508th positions of FGFR2 and FGFR3, respectively. This lysine coordinates the ATP binding site of FGFR, thus hinting at the possible perturbation of FGFR activity by thalidomide. Kinome analysis revealed that kinase activities of FGFR2 and FGFR3 (G697C) reduced by 31% and 65%, respectively, in the presence of 10 μM thalidomide. Further, we checked and confirmed that the analogs inhibited the FGFR2 kinase activity in a dose-dependent manner. This study suggests that FGFRs could be potential targets of thalidomide and the two analogs, and also endorses the link between the teratogenicity and antitumor activities of the drugs.
Insights
Thalidomide and its analogs may target Fibroblast Growth Factor Receptors (FGFRs), potentially linking its teratogenic and anticancer effects. This study investigated drug-protein interactions and FGFR expression modulation.
Area of Science:
- Pharmacology and Molecular Biology
- Developmental Biology and Cancer Research
Background:
- Thalidomide, a known teratogen, is being investigated for anticancer potential.
- Fibroblast Growth Factor Receptors (FGFRs) are crucial in both embryonic development and cancer.
- Similarities between FGFR-related conditions and thalidomide embryopathy suggest a potential drug-target relationship.
Purpose of the Study:
- To investigate the hypothesis that thalidomide targets FGFRs.
- To explore the effects of thalidomide and its analogs on FGFR expression and activity.
- To elucidate the molecular mechanisms underlying thalidomide's teratogenic and potential anticancer effects via FGFRs.
Main Methods:
- Utilized cell lines and a chicken embryo model to assess FGFR expression.
- Employed molecular docking, KINOMEscan analysis, and kinase activity assays to study drug-protein interactions.
- Performed transcriptome analysis on thalidomide-treated chick embryos.
Main Results:
- Thalidomide and analogs differentially regulated FGFR1 and FGFR2 expression in cells and developing organs.
- Molecular docking indicated interactions between analogs and FGFR2/FGFR3 at critical ATP-binding sites.
- Kinome analysis showed significant inhibition of FGFR2 and FGFR3 kinase activity by thalidomide in a dose-dependent manner.
Conclusions:
- FGFRs are identified as potential molecular targets of thalidomide and its analogs.
- The study supports a link between thalidomide's teratogenicity and its antitumor activities through FGFR modulation.
- Findings provide a molecular basis for understanding thalidomide's multifaceted effects.
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