Fibroblast growth factor receptor inhibitors: patent review (2015–2019)

ABSTRACT

Introduction: fibroblast growth factor receptors (FGFRs) are a family of tyrosine-kinase receptors whose signaling cascade regulates cellular proliferation, differentiation, and survival. Deregulation of the FGFR pathway is recognized as a driving factor in tumor development. On this basis, FGFR is an attractive target for anti-cancer small-molecule therapeutic agents.

Areas covered: This review summarizes patent and literature publications spanning from 2015 to 2019 pertaining to small-molecule FGFR kinase inhibitors.

Expert opinion: The first generation of non-covalent FGFR inhibitors is characterized by a broad spectrum of activity and a relatively high toxicity profile. The second generation of FGFR inhibitors shows higher selectivity and a more favorable toxicity profile, but the clinical use appears restricted only to small subsets of cancers strongly dependent on FGFR signaling. Nevertheless, erdafitinib has been approved for the treatment of metastatic urothelial carcinoma, becoming the first marketed selective FGFR inhibitor. The insurgence of mutant kinases, resistant to available therapies, has led to the development of irreversible FGFR inhibitors. The adoption of safer and more selective covalent inhibitors might supersede reversible inhibitors in specific therapeutic areas. Alternative strategies, such as FGF trapping by protein or small-molecule therapeutics, deserve attention and further investigations to unravel their potential.

KEYWORDS:

• Fibroblast growth factor receptor
• cancer
• FGFR inhibitors
• covalent inhibitors

Author contributions

GM collected the relevant literature; GM, AL, MM, and RC read the literature and contributed to the drafting of the manuscript and revising. All authors agree to be accountable for all aspects of the work.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Regione Emilia Romagna, project ‘Oncologia di precisione e nuove terapie antitumorali (ONCOPENTA)’ under grant number 2016-8507/RER.