EZH2 inhibitors: a patent review (2014-2016)

ABSTRACT

Introduction: The histone methyltransferase EZH2 is the catalytic subunit of the PRC2 complex involved in H3K27 trimethylation. Aberrant PRC2 activity has been reported in several cancers and EZH2 overexpression has been associated with poor outcome in different tumors. EZH2 somatic mutations and deletions was found in lymphomas, myelodysplastic and myeloproliferative disorders and associated with higher H3K27me3 levels. Numerous chemical entities have been studied as EZH2 inhibitors in the recent years and some of them entered the cancer clinical arena.

Areas covered: This review summarizes recent efforts in the drug development of EZH2 inhibitors reported in the patent literature covering the 2014–2016 period, and their potential use as therapeutics mainly in cancerous diseases.

Expert opinion: Despite the number of compounds described, only a few of them entered the clinical arena. Moreover, most of the compounds developed share a common 2-pyridone ring pharmacophore. Recently, secondary mutants have been described to be resistant to the standard EZH2 inhibitors treatment. Based on these data a lot of effort is still required to find new chemical entities that inhibit EZH2 directly, or indirectly (via PRC2 disruption). Several issues are still to be settled, such as drug resistance and the importance of selectivity over EZH1 or somatic EZH2 mutants.

KEYWORDS:

• Epigenetics
• polycomb repressive complex 2
• enhancer of zeste homolog 2
• small molecule inhibitors
• cancer

Article highlights

• Drug design strategies for EZH2 inhibitors development as promising therapeutic tools in cancer as well as agents to better investigate the role of EZH2 in non-cancerous diseases;

• A huge number of 2-pyridone-containing compounds have been reported as EZH2-inhibitors so far. Co-crystal structure of PRC2 with an inhibitor and SAR studies assessed the importance of this moiety for the activity as well as its implication in drug resistance development;

• Secondary EZH2 mutations, induced after EZH2i administration, were associated with drug resistance development;

• Novel non-pyridone-based derivatives have been described in some of the recent patents, leading the development of novel classes of compounds possibly overcoming the drug resistance issue;

• EPZ-6438 (tazemetostat) is dominating the clinical arena with several clinical trials on-going, getting EZH2 inhibitors closer to be in the market as drugs

This box summarizes key points contained in the article.

Declaration of interest

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.

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Funding

This paper was funded by European Commission grant number A-PARADDISE/602080 and FP7 Projects BLUEPRINT/282510, additional funding was provided by Sapienza Università di Roma IIT-Sapienza Project, Sapienza Ateneo Project 2014.