Inhibition of FGFR Signaling by Targeting FGF/FGFR Extracellular Interactions: Towards the Comprehension of the Molecular Mechanism through NMR Approaches.

Autor: Pagano K; Istituto di Scienze e Tecnologie Chimiche 'Giulio Natta' (SCITEC), via Corti 12, 20133 Milano, Italy., Longhi E; Laboratory of Tumour Microenvironment, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 24126 Bergamo, Italy., Molinari H; Istituto di Scienze e Tecnologie Chimiche 'Giulio Natta' (SCITEC), via Corti 12, 20133 Milano, Italy., Taraboletti G; Laboratory of Tumour Microenvironment, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 24126 Bergamo, Italy., Ragona L; Istituto di Scienze e Tecnologie Chimiche 'Giulio Natta' (SCITEC), via Corti 12, 20133 Milano, Italy.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2022 Sep 17; Vol. 23 (18). Date of Electronic Publication: 2022 Sep 17.
DOI: 10.3390/ijms231810860
Abstrakt: NMR-based approaches play a pivotal role in providing insight into molecular recognition mechanisms, affording the required atomic-level description and enabling the identification of promising inhibitors of protein-protein interactions. The aberrant activation of the fibroblast growth factor 2 (FGF2)/fibroblast growth factor receptor (FGFR) signaling pathway drives several pathologies, including cancer development, metastasis formation, resistance to therapy, angiogenesis-driven pathologies, vascular diseases, and viral infections. Most FGFR inhibitors targeting the intracellular ATP binding pocket of FGFR have adverse effects, such as limited specificity and relevant toxicity. A viable alternative is represented by targeting the FGF/FGFR extracellular interactions. We previously identified a few small-molecule inhibitors acting extracellularly, targeting FGFR or FGF. We have now built a small library of natural and synthetic molecules that potentially act as inhibitors of FGF2/FGFR interactions to improve our understanding of the molecular mechanisms of inhibitory activity. Here, we provide a comparative analysis of the interaction mode of small molecules with the FGF2/FGFR complex and the single protein domains. DOSY and residue-level NMR analysis afforded insights into the capability of the potential inhibitors to destabilize complex formation, highlighting different mechanisms of inhibition of FGF2-induced cell proliferation.
Databáze: MEDLINE
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