Synthetic lethality: targeting the SMARCA2 bromodomain for degradation in SMARCA4-deficient tumors – a review of patent literature from 2019–June 2023

ABSTRACT

Introduction

SMARCA2 and SMARCA4 are subunits of the SWI/SNF complex which is a chromatin remodeling complex and a key epigenetic regulator that facilitates gene expression. Tumors with loss of function mutations in SMARCA4 rely on SMARCA2 for cell survival and this synthetic lethality is a potential therapeutic strategy to treat cancer.

Areas covered

The current review focuses on patent applications that claim proteolysis-targeting chimeras (PROTAC) degraders that bind the bromodomain site of SMARCA2 and are published between January 2019-June 2023. A total of 29 applications from 9 different applicants were evaluated.

Expert opinion

SMARCA2/4 bromodomain inhibitors do not lead to desired effects on cancer proliferation; however, companies have converted bromodomain binders into PROTACs to degrade the protein, with a preference for SMARCA2 over SMARCA4. Selective degradation of SMARCA2 is most likely required to be efficacious in the SMARCA4-deficient setting, while allowing for sufficient safety margin in normal tissues. With several patent applications disclosed recently, interest in targeting SMARCA2 should continue, especially with a selective SMARCA2 PROTAC now in the clinic from Prelude Therapeutics. The outcome of the clinical trials will influence the evolution of selective SMARCA2 PROTACs development.

KEYWORDS:

• SMARCA2
• BRM
• SMARCA4
• BRG-1
• proteolysis-targeting chimera (PROTAC)
• targeted protein degradation (TPD)
• synthetic lethality
• epigenetics

Article highlights

• Targeting SMARCA2 in SMARCA4 deficient tumors has emerged as a credible synthetic lethality mechanism.

• Use of bromodomain binders to generate bifunctional PROTACs using VHL or CRBN E3 ligase binders was able to accomplish SMARCA2 protein degradation. SMARCA2-selective degraders were generated using nonselective bromodomain binders.

• With a limited number of SMARCA2 binders known, most of the disclosures are limited to pyridazines or modified (cyclized version) pyridazines as target binders with a variety of linkers (flexible and constrained) and known E3 ligase binders for VHL or CRBN.

• Patent applications describing SMARCA2 degraders from January 2019 to June 2023 are collated and analyzed in this article. The material covers 29 applications from 9 different applicants.

• The significant activity in the field has resulted in the first candidate entering the clinic. At the time of writing, PRT3789 has progressed into the clinic and the outcome of the trial will determine the therapeutic potential of selective SMARCA2 degraders in SMARCA4 mutated cancers.

Declaration of interest

The authors are employees and shareholders of AstraZeneca. 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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.