Successes and challenges in the development of BD1-selective BET inhibitors: a patent review

ABSTRACT

Introduction

Bromodomain and ExtraTerminal (BET) domain proteins are transcriptional cofactors that, recognizing acetylated lysines of histone and non-histone proteins, can modulate gene expression. The BET family consists of four members, each of which contains two bromodomains (BD1 and BD2) able to recognize the acetylated mark. Pan-BET inhibitors (BETi) have shown a promising anticancer potential in many clinical trials; however, their further development has been in part hampered by the side effects due to their lack of selectivity. Mounting evidence suggests that BD1 is primarily involved in cancer and that its selective inhibition can phenocopy the anticancer effects of pan-BETi with increased tolerability. Therefore, the development of BD1 selective inhibitors is highly pursed in both academia and industry.

Areas covered

This review aims at giving an overview of the patent literature of BD1-selective BETi between 2014 and 2023. WIPO, USPTO, EPO, and SciFinder® databases were used for the search of patents.

Expert opinion

The development of BD1-selective BETi, despite challenging, is highly desirable as it could have a great impact on the development of new safer anticancer therapeutics. Several strategies could be applied to discover potent and selective compounds with limited side effects.

KEYWORDS:

• Epigenetics
• bromodomains
• BD1
• BET
• cancer
• selective inhibition
• small molecule modulators

Article highlights

• Recent literature overview of BET proteins and their assessment as therapeutic targets.

• Therapeutic potential of BD1-selective inhibitors as anticancer agents with increased tolerability compared to pan-BETi.

• The production of patents in the field of BD1-selective BETi in the period 2014–2023 was analyzed.

• Description of many patents focusing on small-molecule BD1 inhibitors bearing different structural scaffolds, including pyridine, tetrahydroquinoline, benzopiperazine, imidazole, benzimidazole, purine, diazene, diazepine, pyrrole, and compounds with spiro/tricyclic nucleus.

Declaration of interests

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 in this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

Conceptualization, M.V., A.C., C.M., D.R.; writing – original draft preparation, M.V., A.C., A.F., E.F.; writing – review and editing, M.V., A.C., C.M., D.R.; visualization, S.C., A.M., G.S.; supervision, C.M., D.R. S.C., A.M., G.S. All authors have read and agreed to the published version of the manuscript.

Additional information

Funding

This paper was funded by the Italian Ministry of Education, University and Research via a MeDyCa grant (FISR2019 00374) (A. Mai) and by the funding from the European Union - NextGenerationEU through the Italian Ministry of University and Research under PNRR - M4C2-I1.3 Project PE_00000019 “HEAL ITALIA” to Dante Rotili CUP (B53C22004000006). The views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be held responsible for them.