Synthetic lethality: targeting SMARCA2 ATPase in SMARCA4-deficient tumors – a review of patent literature from 2019–30 June 2023

ABSTRACT

Introduction

The multi-subunit SWI/SNF chromatin remodeling complex is a key epigenetic regulator for many cellular processes, and several subunits are found to be mutated in human cancers. The inactivating mutations of SMARCA4, the ATPase subunit of the complex, result in cellular dependency on the paralog SMARCA2 for survival. This observed synthetic lethal relationship posits targeting SMARCA2 in SMARCA4-deficient settings as an attractive therapeutic target in oncology.

Areas covered

This review covers patent literature disclosed during the 2019–30 June 2023 period which claim ATPase inhibitors and PROTAC degraders that bind to the ATPase domain of SMARCA2 and/or SMARCA4. A total of 16 documents from 6 applicants are presented.

Expert opinion

The demonstration of cellular dependence on SMARCA2 ATPase activity in SMARCA4-deficient settings has prompted substantial research toward SMARCA2-targeting therapies. Although selectively targeting the ATPase domain of SMARCA2 is viewed as challenging, several ATPase inhibitor scaffolds have been disclosed within the last five years. Most early compounds are weakly selective, but these efforts have culminated in the first dual SMARCA2/SMARCA4 ATPase inhibitor to enter clinical trials. Data from the ongoing clinical trials, as well as continued advancement of SMARCA2-selective ATPase inhibitors, are anticipated to significantly impact the field of therapies, targeting SMARCA4-deficient tumors.

KEYWORDS:

• SMARCA2
• SMARCA4
• BRM
• BRG1
• ATPase inhibitor
• synthetic lethality
• epigenetics
• SWI/SNF complex

Article highlights

• Inhibition of SMARCA2 ATPase activity is an attractive synthetic lethality approach to treat SMARCA4-mutant or -deficient cancers.

• Interest in inhibiting the ATPase activity of SMARCA2 via small molecules has increased in the past several years based on the number of patent documents claiming SMARCA2 ATPase inhibitors.

• This review aims to highlight patent literature which claim small molecule ATPase inhibitors as well as ATPase targeting PROTAC degraders of SMARCA2 and/or SMARCA4 during the 2019-30 June 2023 period.

• The first dual inhibitor of SMARCA2 and SMARCA4 (FHD-286) entered Phase I clinical trials in 2021 to treat relapsed/refractory acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) and metastatic uveal melanoma. The results of these studies will inform the future development of SMARCA2/SMARCA4 inhibitors for the treatment of disorders associated with the SWI/SNF complex.

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.

Author contribution statement

The conception of the article was by A.G. K.D.R., E.C.Y.L, and A.G. all contributed to the writing of this manuscript.

Additional information

Funding

This paper was not funded.