Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Abstract

SWI/SNF enzymes are heterogeneous multi-subunit complexes that utilize the energy from ATP hydrolysis to remodel chromatin structure, facilitating transcription, DNA replication, and repair. In mammalian cells, distinct sub-complexes, including cBAF, ncBAF, and PBAF exhibit varying subunit compositions and have different genomic functions. Alterations in the SWI/SNF complex and sub-complex functions are a prominent feature in cancer, making them attractive targets for therapeutic intervention. Current strategies in cancer therapeutics involve the use of pharmacological agents designed to bind and disrupt the activity of SWI/SNF complexes or specific sub-complexes. Inhibitors targeting the catalytic subunits, SMARCA4/2, and small molecules binding SWI/SNF bromodomains are the primary approaches for suppressing SWI/SNF function. Proteolysis-targeting chimeras (PROTACs) were generated by the covalent linkage of the bromodomain or ATPase-binding ligand to an E3 ligase-binding moiety. This engineered connection promotes the degradation of specific SWI/SNF subunits, enhancing and extending the impact of this pharmacological intervention in some cases. Extensive preclinical studies have underscored the therapeutic potential of these drugs across diverse cancer types. Encouragingly, some of these agents have progressed from preclinical research to clinical trials, indicating a promising stride toward the development of effective cancer therapeutics targeting SWI/SNF complex and sub-complex functions.

Keywords: DNA damage; PROTACs; SWI/SNF chromatin-remodeling complexes; allosteric ATPAse inhibitors; bromodomain inhibitors; cancer; epigenetics; transcription.

Figure 1

SWI/SNF Chromatin-Remodeling Complexes. Different SWI/SNF complexes exist in the form of cBAF, PBAF, and ncBAF. Yellow: SMARCA4 and SMARCA2 catalytic subunits. Purple: cBAF specific subunits. Green: PBAF specific subunits. Red: ncBAF specific subunits. Blue: subunits that assemble into all three complexes. Grey: subunits that assemble into cBAF and PBAF. Orange: subunits that assemble into cBAF and ncBAF.

Figure 2

SWI/SNF subunits and the targeted domains. The most frequent approaches to inhibiting SWI/SNF function include the following: (A) Inhibition of the SMARCA4/SMARCA2 ATPase or inhibition of the SMARCA4 and SMARCA2 bromodomains with Family VIII inhibitors. (B) Family VIII inhibitors also bind to PBRM1 bromodomains. There are also several PBRM1-selective inhibitors. (C,D) Family IV bromodomain inhibitors bind to BRD7 and BRD9 bromodomains with varying selectivity for BRD9 or BRD7.