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Updated: Jan 23, 2026
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design
William Farnaby1, Manfred Koegl2, Michael J Roy1
1Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK.
Abstract:
Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.
Insights
Researchers developed novel PROTAC degraders targeting SMARCA2 and SMARCA4 proteins, crucial for cancer cell growth. This approach shows promise for developing new cancer therapies by exploiting vulnerabilities in BAF/PBAF chromatin remodeling complexes.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- BAF/PBAF chromatin remodeling complexes are implicated in cancer.
- Targeting ATPase subunits of these complexes presents a potential therapeutic strategy.
Purpose of the Study:
- To develop proteolysis targeting chimera (PROTAC) degraders for SMARCA2 and SMARCA4.
- To investigate the efficacy of these degraders in cancer models.
Main Methods:
- Design and synthesis of PROTAC molecules utilizing a bromodomain ligand and VHL E3 ligase recruitment.
- Structure-based drug design and biophysical characterization.
- Assessment of anti-proliferative effects and cell death induction in cancer cell lines.
Main Results:
- Developed ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4, and PBRM1.
- ACBI1 induced anti-proliferative effects and cell death via SMARCA2 depletion in SMARCA4 mutant cancer cells.
- Demonstrated efficacy in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity.
Conclusions:
- Biophysics- and structure-based PROTAC design is effective for degrading challenging targets like BAF/PBAF subunits.
- ACBI1 represents a promising therapeutic candidate for tumors sensitive to BAF complex ATPase loss.
- This work paves the way for novel therapeutics targeting chromatin remodeling complexes in cancer.
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