Targeting PRC2 for the treatment of cancer: an updated patent review (2016 - 2020)

ABSTRACT

Introduction

PRC2 is a histone methyltransferase complex associated with several cancer types. Tazemetostat was recently approved as the first inhibitor targeting the catalytic subunit EZH2 and several other EZH2 inhibitors are now under clinical evaluation. Beyond EZH2, researchers have also explored other approaches including PRC2 activators, dual agents inhibiting both EZH1 and EZH2, allosteric inhibitors binding to EED, and compounds which induce the degradation of PRC2 constituent proteins.

Areas covered

This review provides an overview of anticancer therapies targeting PRC2 during the period 2016–2020 including clinical trials, patents and the scientific literature.

Expert opinion

The approval of tazemetostat marks the clinical validation of EZH2 for the treatment of cancer. Despite this success many questions remain; for instance, tazemetostat was briefly placed on clinical hold for safety concerns, while another EZH2 inhibitor (GSK126) demonstrated insufficient efficacy during a Phase I/II trial. It is important to understand these risks as PRC2 therapies progress through clinic evaluation. Alternative approaches to target PRC2 may offer distinct advantages over the inhibition of EZH2, including the potential to overcome EZH2 resistance mutations. However, these emerging modalities may also incur new challenges as they progress toward the clinic. Nonetheless, the diversity of agents under development represents a wealth of therapeutic options for future patients.

KEYWORDS:

• PRC2
• EED
• EZH2
• PROTACs
• cancer
• epigenetics
• oncology

Article highlights

• Since 2016 over 35 clinical trials have been initiated evaluating six EZH2 inhibitors; the highlights are featured in this review.

• The first EZH2 inhibitor (Tazemetostat) was approved by the FDA in January 2020 for treatment of epithelioid sarcoma and follicular lymphoma, and is currently being evaluated in additional clinical settings.

• Valematostat is the first dual EZH1/EZH2 agent to enter the clinic and has gained special priority for further development, earning accelerated ‘Sakigake’ designation in Japan.

• Several organizations have recently reported compounds which bind to the EED subunit of PRC2 and subsequently result in modulation of the histone methyltransferase activity of EZH2.

• MAK683 (Novartis) is the first EED binder to progress to clinical evaluation, and is currently in Phase I/II trials for DLBCL, nasopharyngeal carcinoma (NPC) or other advanced solid tumors where no further effective standard treatment is available.

• In addition to inhibitors targeting EZH2 and EED, new modes of action have continued to emerge including PRC2 activators and bifunctional degraders, further increasing the range of modalities available to target PRC2.

• This box summarizes key points contained in the article.

Acknowledgments

The authors acknowledge the contributions of Dr Kurt Pike, Dr Jamie Scott and Dr Tom Heightman for feedback/guidance on writing the manuscript. They also acknowledge Dr Mathew Horrocks, the academic supervisor for Milly Dockerill.

Declaration of interest

DH O’ Donovan, C Gregson and M Dockerill are employees of AstraZeneca PLC. DH O’ Donovan and C Gregson are shareholders of AstraZeneca PLC. 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. 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 not funded.