A patent review of FGFR4 selective inhibition in cancer (2007-2018)

ABSTRACT

Introduction: FGFR4 is a tyrosine kinase receptor which, under physiological conditions, is activated upon ligand binding in a highly regulated manner. This triggers downstream signaling related to proliferation and apoptosis resistance as well as other physiological processes. Many molecular alterations of the receptor and its ligands, specially FGF19, have been reported in several types of cancer, with special relevance in hepatocellular carcinoma. In addition, these have also been detected in other solid malignancies, including lung, breast, or colon cancer, among others.

Areas covered: This review covers patent literature on specific FGFR4 inhibitors and their applications, published from 2007 to June 2018.

Expert opinion: FGFR4 inhibition has gained relevance in oncology. A considerable number of patents disclosing different approaches to inhibit this receptor have been reported, displaying promising preclinical results for different cancer models. Currently, the safety and preliminary efficacy of several small molecule inhibitors targeting FGFR4 are under early phase clinical assessment, mainly in hepatocellular carcinoma patients. If positive results are derived from these trials, they will open the door for the application of FGFR4 small molecule inhibitors to a wide population of tumors of different types that harbor FGFR4-FGF19 signaling dysregulation.

Trial registration: ClinicalTrials.gov identifier: NCT02325739.

Trial registration: ClinicalTrials.gov identifier: NCT02834780.

Trial registration: ClinicalTrials.gov identifier: NCT03144661.

Trial registration: ClinicalTrials.gov identifier: NCT02508467.

KEYWORDS:

• FGFR4
• cancer
• inhibitor
• hepatocellular carcinoma

Article highlights

• Patented selective FGFR4 inhibitors and their use, as described in reports made from 2007-June 2018 are discussed.

• FGFR4 is a well-known oncogenic driver in hepatocellular carcinoma; its tumorigenic role has been extended to other tumor types in recent years.

• FGFR4 inhibition has shown promising results in preclinical models of hepatocellular carcinoma and other tumor types.

• Different types of drugs targeting FGFR4, such as small molecule inhibitors, therapeutic antibodies and peptides, and their combination with other therapeutic agents are discussed.

This box summarizes key points contained in the article.

Declaration of interest

L Paz Ares was supported by ISCIII (PI14/01964, PIE15/00076, PI17/00778 and DTS17/00089) and CIBERONC (CD16/12/00442), and co-funded by FEDER from Regional Development European Funds (European Union). L Paz Ares also reports personal fees from Roche, Lilly, MSD, BMS, Astra Zeneca, Boehringer Ing., Pfizer, Takeda, Novartis, Merck Serono and Amgem, outside the submitted work. In addition, L Paz Ares has patent P201730928 and patent PCT/ES2018/070502 pending. I Ferrer was supported by AECC (AIO2015) and Consejería de Igualdad, Salud y Políticas Sociales de la Junta de Andalucía (PI-0029-2013) and ISCIII (PI16/01311) and cofunded by FEDER from Regional Development European Funds (European Union). Also, I Ferrer has patent P201730928 and patent PCT/ES2018/070502 pending. S Molina-Pinelo was supported by the Consejería de Salud y Bienestar Social of Junta de Andalucía through the ‘“Nicolás Monardes”’ program [C-0040-2016] and ISCIII (PI17/00033) and co-funded by FEDER from Regional Development European Funds (European Union). Also, S Molina-Pinelo has patent P201730928 and patent PCT/ES2018/070502 pending. A Quintanal-Villalonga has patent P201730928 and patent PCT/ES2018/070502 pending. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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