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

Sundaresan, Lakshmikirupa; Kumar, Pranav; Manivannan, Jeganathan; Balaguru, Uma Maheswari; Kasiviswanathan, Dharanibalan; Veeriah, Vimal; Anishetty, Sharmila; Chatterjee, Suvro

doi:10.1021/acs.chemrestox.8b00286

Cited by 10 publications

(4 citation statements)

References 58 publications

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“…We analysed our previously published KINOMEscan kinase screening dataset of thalidomide 33 in order to investigate how thalidomide affects the immune system. Kinases whose activities were reduced at least by 60% were considered for further enrichment analysis.…”

Section: Methodsmentioning

confidence: 99%

Repurposing of thalidomide and its derivatives for the treatment of SARS‐coV‐2 infections: Hints on molecular action

Sundaresan

Giri

Singh

et al. 2021

Brit J Clinical Pharma

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Aims The SARS‐coV‐2 pandemic continues to cause an unprecedented global destabilization requiring urgent attention towards drug and vaccine development. Thalidomide, a drug with known anti‐inflammatory and immunomodulatory effects has been indicated to be effective in treating a SARS‐coV‐2 pneumonia patient. Here, we study the possible mechanisms through which thalidomide might affect coronavirus disease‐19 (COVID‐19). Methods The present study explores the possibility of repurposing thalidomide for the treatment of SARS‐coV‐2 pneumonia by reanalysing transcriptomes of SARS‐coV‐2 infected tissues with thalidomide and lenalidomide induced transcriptomic changes in transformed lung and haematopoietic models as procured from databases, and further comparing them with the transcriptome of primary endothelial cells. Results Thalidomide and lenalidomide exhibited pleiotropic effects affecting a range of biological processes including inflammation, immune response, angiogenesis, MAPK signalling, NOD‐like receptor signalling, Toll‐like receptor signalling, leucocyte differentiation and innate immunity, the processes that are aberrantly regulated in severe COVID‐19 patients. Conclusion The present study indicates thalidomide analogues as a better fit for treating severe cases of novel viral infections, healing the damaged network by compensating the impairment caused by the COVID‐19.

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Section: Methodsmentioning

confidence: 99%

Repurposing of thalidomide and its derivatives for the treatment of SARS‐coV‐2 infections: Hints on molecular action

Sundaresan

Giri

Singh

et al. 2021

Brit J Clinical Pharma

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“…This allowed docking to be performed, the results showing a good fit of thalidomide to this receptor (with RMSD values ranging from 0.349 to 1.133, scores ranged from -9.9 to -9.1 kcal/mol) (Lagarde et al, 2018). Another study showed that fibroblast growth factor receptors (FGFRs), involved in embryo development and cancer pathophysiology, could be potential targets of thalidomide and its analogs, also endorsing the link between the teratogenicity and antitumor activities of these drugs (Sundaresan et al, 2019).…”

Section: Thalidomidementioning

confidence: 98%

Repurposing old drugs to fight multidrug resistant cancers

Dinić

Efferth

García-Sosa

et al. 2020

Drug Resistance Updates

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Overcoming multidrug resistance represents a major challenge for cancer treatment.In the search for new chemotherapeutics to treat malignant diseases, drug repurposing gained a tremendous interest during the past years. Repositioning candidates have often emerged through several stages of clinical drug development, and may even be marketed, thus attracting the attention and interest of pharmaceutical companies as well as regulatory agencies. Typically, drug repositioning has been serendipitous, using undesired side effects of small molecule drugs to exploit new disease indications. As bioinformatics gain increasing popularity as an integral component of drug discovery, more rational approaches are needed. Herein, we show some practical examples of in silico approaches such as pharmacophore modelling, as well as pharmacophore-and docking-based virtual screening for a fast and cost-effective repurposing of small molecule drugs against multidrug resistant cancers. We provide a timely and comprehensive overview of compounds with considerable potential to be repositioned for cancer therapeutics. These drugs are from diverse chemotherapeutic classes. We emphasize the scope and limitations of anthelmintics, antibiotics, antifungals, antivirals, antimalarials, antihypertensives, psychopharmaceuticals and antidiabetics that have shown extensive immunomodulatory, antiproliferative, proapoptotic, and antimetastatic potential. These drugs, either used alone or in combination with existing anticancer chemotherapeutics, represent strong candidates to prevent or overcome drug resistance. We particularly focus on outcomes and future perspectives of drug repositioning for the treatment of multidrug resistant tumors and discuss current possibilities and limitations of preclinical and clinical investigations.

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“…It is via this pathway that retinoids, including the potent congener isotretinoin, improve both Apert and nonsyndromic acne [ 79 , 80 ]. The same pharmacologic FGFR2-blocking mechanism likely causes the dysmorphogenetic teratogenicity of this drug, as well as of thalidomide [ 81 ].…”

Section: Main Textmentioning

confidence: 99%

2b or Not 2b: How Opposing FGF Receptor Splice Variants Are Blocking Progress in Precision Oncology

Epstein

Liao²,

Gu³

2021

Journal of Oncology

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More than ten thousand peer-reviewed studies have assessed the role of fibroblast growth factors (FGFs) and their receptors (FGFRs) in cancer, but few patients have yet benefited from drugs targeting this molecular family. Strategizing how best to use FGFR-targeted drugs is complicated by multiple variables, including RNA splicing events that alter the affinity of ligands for FGFRs and hence change the outcomes of stromal-epithelial interactions. The effects of splicing are most relevant to FGFR2; expression of the FGFR2b splice isoform can restore apoptotic sensitivity to cancer cells, whereas switching to FGFR2c may drive tumor progression by triggering epithelial-mesenchymal transition. The differentiating and regulatory actions of wild-type FGFR2b contrast with the proliferative actions of FGFR1 and FGFR3, and may be converted to mitogenicity either by splice switching or by silencing of tumor suppressor genes such as CDH1 or PTEN. Exclusive use of small-molecule pan-FGFR inhibitors may thus cause nonselective blockade of FGFR2 isoforms with opposing actions, undermining the rationale of FGFR2 drug targeting. This splice-dependent ability of FGFR2 to switch between tumor-suppressing and -driving functions highlights an unmet oncologic need for isoform-specific drug targeting, e.g., by antibody inhibition of ligand-FGFR2c binding, as well as for more nuanced molecular pathology prediction of FGFR2 actions in different stromal-tumor contexts.

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

Cited by 10 publications

References 58 publications

Repurposing of thalidomide and its derivatives for the treatment of SARS‐coV‐2 infections: Hints on molecular action

Repurposing of thalidomide and its derivatives for the treatment of SARS‐coV‐2 infections: Hints on molecular action

Repurposing old drugs to fight multidrug resistant cancers

2b or Not 2b: How Opposing FGF Receptor Splice Variants Are Blocking Progress in Precision Oncology

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