Thalidomide and Its Analogs Differentially Target Fibroblast Growth Factor Receptors: Thalidomide Suppresses FGFR Gene Expression while Pomalidomide Dampens FGFR2 Activity

• Published in: Chemical research in toxicology 2019-04, Vol.32 (4), p.589-602
• Main Authors: Sundaresan, Lakshmikirupa, Kumar, Pavitra, Manivannan, Jeganathan, Balaguru, Uma Maheswari, Kasiviswanathan, Dharanibalan, Veeriah, Vimal, Anishetty, Sharmila, Chatterjee, Suvro
• Format: Article
• Language: English
• Subjects: Animals; Cell Survival - drug effects; Cells, Cultured; Chick Embryo; Chickens; Dose-Response Relationship, Drug; Gene Expression Profiling; Humans; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Receptors, Fibroblast Growth Factor - antagonists & inhibitors; Receptors, Fibroblast Growth Factor - genetics; Receptors, Fibroblast Growth Factor - metabolism; Structure-Activity Relationship; Thalidomide - analogs & derivatives; Thalidomide - chemistry; Thalidomide - pharmacology
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/acs.chemrestox.8b00286

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.