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.
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.