A patent review of EZH2 inhibitors from 2017 and beyond

ABSTRACT

Introduction

EZH2 is an important epigenetic regulator that forms the PRC2 complex with SUZ12, EED and RbAp46/48. As the key catalytic subunit of PRC2, EZH2 regulates the trimethylation of histone H3K27, which in turn promotes chromatin condensation and represses the transcription of relevant target genes. EZH2 overexpression and mutations are strictly related to tumor proliferation, invasion and metastasis. Currently, a large number of highly specific EZH2 inhibitors have been developed and some have already been in clinical trials.

Areas covered

The aim of the present review is to provide an overview of the molecular mechanisms of EZH2 inhibitors and to highlight the research advances in the patent literature published from 2017 to date. A search of the literature and patents for EZH2 inhibitors and degraders was performed using the Web of Science, SCIFinder, WIPO, USPTO, EPO and CNIPA databases.

Expert opinion

In recent years, a great number of structurally diverse EZH2 inhibitors have been identified, including EZH2 reversible inhibitors, EZH2 irreversible inhibitors, EZH2-based dual inhibitors and EZH2 degraders. Despite the multiple challenges, EZH2 inhibitors offer promising potential for the treatment of various diseases, such as cancers.

KEYWORDS:

• Cancer
• Degrader
• EZH2 inhibitor
• Patent
• Tazemetostat

Article highlights

• EZH2 protein plays crucial roles in cancer and has emerged as promising drug target.

• EZH2 inhibitor patents ranging from 2017 to date are reviewed and summarized.

• Many drug design strategies such as covalent binding and dual-target inhibition have been used in the development of novel EZH2 inhibitors.

• New PROTAC technology has been harnessed to target EZH2 protein for degradation.

Nomenclature

CI	=	combination index
EED	=	Embryonic Ectoderm Development
EZH2	=	Enhancer of Zeste Homologous 2
LTR	=	long-terminal repeat
PRC2	=	Polycomb Repressive Complex 2
Rb Ap46/48	=	Retinoblastoma-associated proteins 46/48
SAH	=	S-adenosyl homocysteine
SAM	=	S-adenosyl methionine
SET	=	Su(var.) 3–9, enhancer of zeste and trithorax
SUZ12	=	Suppressor of Zeste 12
TNBC	=	triple negative breast cancer

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.

Author’s contributions

GQ Wan, H Feng, Chang Su, YX Zhu and LD Zhang have contributed in searching the patent literature. GQ Wan and H Feng have analyzed and classified the compounds. GQ Wan, QS Zhang and LT Yu have designed and written the manuscript.

Additional information

Funding

This paper was funded by the National Natural Science Foundation of China (82073687), and Science and Technology Program of Sichuan Province (2021YFH0145).