A patent review of BRAF inhibitors: 2013-2018

ABSTRACT

Introduction: As a key element in arguably the most important pathway MAPK signaling, the BRAF kinase gives rise to severe diseases including cancers when pathologically activated. Extensive research on BRAFi (BRAF inhibitor) has been carried out to profile the characters for optimized agents and to elaborate the therapeutic strategies for the related cancer treatment.

Areas covered: This review gives an overview of recently approved BRAF agents on function mode, therapeutic efficacy, and deficiency, based on which current challenges and corresponding strategies were presented. New entities as BRAFi for medical purpose in patent literature during the period 2013–2018 were also briefly introduced.

Expert opinion: With the disclosure of paradox-breaker BRAFi PLX7904 crystal in complex with BRAF, the rational design for next-generation BRAFi is becoming ever more feasible. Accompanying therapeutic strategies in BRAFi elaboration may also provide flexible choice in the future ‘personal medicine’. Further digging in the greatly enriched BRAFi pool will greatly benefit the drug design processes such as FBDD- and SBDD-driven development.

Trial registration: ClinicalTrials.gov identifier: NCT02012231.

Trial registration: ClinicalTrials.gov identifier: NCT02428712.

Trial registration: ClinicalTrials.gov identifier: NCT02014116.

KEYWORDS:

• Anti-tumor
• BRAFi
• combination
• pan-RAF
• paradox-breaker
• paradoxical effect
• resistance

Article highlights

• B-Raf kinase, as a key element in MAPK signaling, is considered a compelling target in oncology

• BRAFi patented from 2013 to 2018 were collected and classified according to the type of inhibition and chemical structure

• Seeking paradox breakers and combining BRAFi with other agents both can delay and/or overcome resistance effectively

• Identification of new BRAFi provides interesting insight exploring into new chemotypes

This box summarizes key points contained in the article.

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 paper was funded by the International Postdoctoral Exchange Fellowship Program 2017 (No. 20170090), National Natural Science Foundation of China (U1204806), Henan Province Postdoctoral Science Foundation (1902001) and Henan Medical Science and Technology Program (2018020601).