BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design
Open accessAbstract
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.
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When ineffectual bromodomain ligands were furnished into PROTAC targeting warheads, potent and selective degradation could be achieved.
“When ineffectual bromodomain ligands were furnished into PROTAC targeting warheads, potent and selective degradation could be achieved.45−47”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [46]
Published co-crystal structures and TR-FRET data previously validated the importance of VHLR69 in SMARCA2BD recognition within the ternary complex.
“In support of this, published co-crystal structures and TR-FRET data previously validated the importance of VHLR69 in SMARCA2BD recognition within the ternary complex35.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [35]
Many effective PROTACs exhibit cooperativity in assembling the components of the ternary complex, implying the presence of adventitious favorable interactions between the target protein and the E3 ligase in the ternary complex.
“The observation that many effective PROTACs exhibit cooperativity in assembling the components of the ternary complex 35, 52, 53 implies the presence of adventitious favorable interactions between the target protein and the E3 ligase in the ternary complex.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [35]
There are not yet enough published crystal structures of ternary complexes to allow for a thorough and rigorous evaluation of the method.
“While there have been several published crystal structures of ternary complexes 35, 52, 54, there are not yet enough to allow for a thorough and rigorous evaluation of our method.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [35]
SMARCA2/4 bromodomain inhibitors have failed to inhibit tumor cell growth because the ATPase domain but not the bromodomain is essential for tumor cell growth.
“However, such inhibitors have failed to inhibit tumor cell growth [48] because the ATPase domain but not the bromodomain is essential for tumor cell growth [169].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [48]
ACBI1 potently induced SMARCA2/4 and PBRM1 degradation in AML cell line and inhibited cell growth in multiple cancer cell lines.
“ACBI1 potently induced SMARCA2/4 and PBRM1 degradation in the AML cell line, and inhibited cell growth in multiple cancer cell lines [48].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [48]
Aromatic, heterocyclic, and macrocyclic linker structures have been reported to minimize unfavorable conformations.
“Aromatic, heterocyclic, and macrocyclic linker structures have been reported to minimize unfavorable conformations [37, 78].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [78]
Farnaby et al. replaced the PEG unit of a lead PROTAC targeting SMARCA2 with a phenyl ring, which recapitulated the geometry of the more flexible linker and formed an additional T-stack interaction to Y98 of VHL.
“they replaced the PEG unit of a lead PROTAC targeting SMARCA2 with a phenyl ring, which recapitulated the geometry of the more flexible linker and formed an additional T-stack interaction to Y98 of VHL [78].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [78]
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Targeted degradation of the enhancer lysine acetyltransferases CBP and p300
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Haven't got a glue: Protein surface variation for the design of molecular glue degraders
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Discovery of SHP2-D26 as a First, Potent, and Effective PROTAC Degrader of SHP2 Protein
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Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity
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Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders
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Self-citationProteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies
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Self-citationPROTAC degraders as chemical probes for studying target biology and target validation
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- Authors
- Farnaby, W., Koegl, M., Roy, M. J., Whitworth, C., Diers, E., Trainor, N., Zollman, D., Steurer, S., Karolyi-Oezguer, J., Riedmueller, C., Gmaschitz, T., Wachter, J., Dank, C., Galant, M., Sharps, B., Rumpel, K., Traxler, E., Gerstberger, T., Schnitzer, R., Petermann, O., Greb, P., Weinstabl, H., Bader, G., Zoephel, A., Weiss-Puxbaum, A., Ehrenhöfer-Wölfer, K., Wöhrle, S., Boehmelt, G., Rinnenthal, J., Arnhof, H., Wiechens, N., Wu, M.-Y., Owen-Hughes, T., Ettmayer, P., Pearson, M., McConnell, D. B., & Ciulli, A.
- Affiliations
- University of Dundee (GB)
- Boehringer Ingelheim (Austria) (AT)
- Corresponding author
- McConnell, Darryl B.
- Ciulli, Alessio
- ORCID
- Farnaby, William
- Koegl, Manfred
- Roy, Michael J.
- Whitworth, Claire
- Diers, Emelyne
- Trainor, Nicole
- Zollman, David
- Dank, Christian
- Rumpel, Klaus
- Gerstberger, Thomas
- Greb, Peter
- Weinstabl, Harald
- Bader, Gerd
- Zoephel, Andreas
- Ehrenhöfer-Wölfer, Katharina
- Wöhrle, Simon
- Boehmelt, Guido
- Rinnenthal, Joerg
- Ettmayer, Peter
- Pearson, Mark
- McConnell, Darryl B.
- Ciulli, Alessio
- Venue
- Nature Chemical Biology
- Published
- 2019-06-10
- Volume
- 15
- Issue
- 7
- Pages
- 672-680
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC6600871
- OpenAlex
- W2948220248
- Cited by
- 562
- References
- 54
- Citations by year
- 2026: 62 · 2025: 95 · 2024: 91 · 2023: 80 · 2022: 72 · 2021: 74 · 2020: 67 · 2019: 20
- FWCI
- 19.53
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-07-02)
- Open access
- Licence
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (acceptedVersion, other-oa)
- PubMed Central (acceptedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- Funders
- Wellcome Trust (100476, 094090/Z/10/Z, 094090, 097945/C/11/Z, 097945, 100476/Z/12/Z)
- Diamond Light Source (MX14980)
- FP7 Ideas: European Research Council (311460)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PROTAC degraders, BAF chromatin remodeling complex, SMARCA2, SMARCA4, PBRM1, VHL E3 ubiquitin ligase, ternary complex crystal structure, structure-based drug design, acute myeloid leukemia, cancer vulnerability, protein degradation
- MeSH terms
- Cells, Cultured, DNA-Binding Proteins, Humans, Nuclear Proteins, Molecular Structure, Leukemia, Myeloid, Acute, Chromatin Assembly and Disassembly, Cell Proliferation
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