Structure-Based Design Identifies PROTAC Degraders of BAF Complex Subunits

Mutations affecting the BAF (SWI/SNF) chromatin-remodeling complex are frequently detected in human cancers. The BAF complex contains one of two mutually exclusive ATPase subunits, SMARCA2 (also known as BRM) and SMARCA4 (also known as BRG1), and selective suppression of SMARCA2 has been suggested as a potential therapeutic strategy for tumors harboring inactivating SMARCA4 mutations. However, specific small-molecule inhibitors targeting the SMARCA2 bromodomain are ineffective, as it is the ATPase domain that is functionally relevant. Farnaby, Koegl, and colleagues sought to selectively target the bromodomains of SMARCA2 and SMARCA4 for protein degradation using structure-based design of proteolysis-targeting chimeras (PROTAC), which link a target-binding ligand to an E3 ligase–binding ligand to recruit the ubiquitin proteasome system. Analysis of co-crystal structures guided the design of a small series of PROTACs consisting of a SMARCA2/4 bromodomain-binding ligand and a known high-affinity ligand for the von Hippel Lindau (VHL) E3 ubiquitin ligase. This approach generated a prototype compound that formed cooperative ternary complexes with the SMARCA2 bromodomain and the VHL–elongin B–elongin C complex and induced partial degradation of SMARCA2/4. Further structure-guided optimization of this initial molecule yielded PROTACs with improved cellular permeability and more effective induction of SMARCA2/4 degradation. In particular, ACBI1 showed enhanced cooperativity and complex stability, and triggered complete degradation of SMARCA2, SMARCA4, and the PBAF complex member PBRM1 with minimal downregulation of other proteins. ACBI1 inhibited cell proliferation and induced apoptosis of both leukemia cell lines with an intact BAF complex and SMARCA4-mutant cancer cells; this effect phenocopied the effect of genetic deletion of SMARCA2/4 and was mediated by on-target degradation of SMARCA2 and SMARCA4. Collectively, this work supports the use of a structure-based approach in designing PROTAC degraders and suggests targeted degradation of BAF complex ATPases as a potential therapeutic strategy.

Farnaby W, Koegl M, Roy MJ, Whitworth C, Diers E, Trainor N, et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat Chem Biol 2019 Jun 10 [Epub ahead of print].

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