BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design

William Farnaby, Manfred Koegl, Michael J. Roy, Claire Whitworth, Emelyne Diers, Nicole Trainor, David Zollman, Steffen Steurer, Jale Karolyi-Oezguer, Carina Riedmueller, Teresa Gmaschitz, Johannes Wachter, Christian Dank, Michael Galant, Bernadette Sharps, Klaus Rumpel, Elisabeth Traxler, Thomas Gerstberger, Renate Schnitzer, Oliver PetermannPeter Greb, Harald Weinstabl, Gerd Bader, Andreas Zoephel, Alexander Weiss-Puxbaum, Katharina Ehrenhöfer-Wölfer, Simon Wöhrle, Guido Boehmelt, Joerg Rinnenthal, Heribert Arnhof, Nicola Wiechens, Meng-Ying Wu, Tom Owen-Hughes, Peter Ettmayer, Mark Pearson, Darryl B. McConnell, Alessio Ciulli

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)672-680
Number of pages9
JournalNature Chemical Biology
Volume15
Issue number7
Early online date10 Jun 2019
DOIs
Publication statusPublished - Jul 2019

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Proteolysis
Adenosine Triphosphatases
Biophysics
Neoplasms
Chromatin Assembly and Disassembly
Ubiquitin-Protein Ligases
Myeloid Cells
Acute Myeloid Leukemia
Cell Death
Ligands
Pharmaceutical Preparations
Therapeutics

Cite this

Farnaby, William ; Koegl, Manfred ; Roy, Michael J. ; Whitworth, Claire ; Diers, Emelyne ; Trainor, Nicole ; Zollman, David ; Steurer, Steffen ; Karolyi-Oezguer, Jale ; Riedmueller, Carina ; Gmaschitz, Teresa ; Wachter, Johannes ; Dank, Christian ; Galant, Michael ; Sharps, Bernadette ; Rumpel, Klaus ; Traxler, Elisabeth ; Gerstberger, Thomas ; Schnitzer, Renate ; Petermann, Oliver ; Greb, Peter ; Weinstabl, Harald ; Bader, Gerd ; Zoephel, Andreas ; Weiss-Puxbaum, Alexander ; Ehrenhöfer-Wölfer, Katharina ; Wöhrle, Simon ; Boehmelt, Guido ; Rinnenthal, Joerg ; Arnhof, Heribert ; Wiechens, Nicola ; Wu, Meng-Ying ; Owen-Hughes, Tom ; Ettmayer, Peter ; Pearson, Mark ; McConnell, Darryl B. ; Ciulli, Alessio. / BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. In: Nature Chemical Biology. 2019 ; Vol. 15, No. 7. pp. 672-680.
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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.",
author = "William Farnaby and Manfred Koegl and Roy, {Michael J.} and Claire Whitworth and Emelyne Diers and Nicole Trainor and David Zollman and Steffen Steurer and Jale Karolyi-Oezguer and Carina Riedmueller and Teresa Gmaschitz and Johannes Wachter and Christian Dank and Michael Galant and Bernadette Sharps and Klaus Rumpel and Elisabeth Traxler and Thomas Gerstberger and Renate Schnitzer and Oliver Petermann and Peter Greb and Harald Weinstabl and Gerd Bader and Andreas Zoephel and Alexander Weiss-Puxbaum and Katharina Ehrenh{\"o}fer-W{\"o}lfer and Simon W{\"o}hrle and Guido Boehmelt and Joerg Rinnenthal and Heribert Arnhof and Nicola Wiechens and Meng-Ying Wu and Tom Owen-Hughes and Peter Ettmayer and Mark Pearson and McConnell, {Darryl B.} and Alessio Ciulli",
note = "partially supported by a European Research Council (ERC) Starting Grant (grant agreement no. ERC-2012-StG-311460 DrugE3CRLs). Biophysics, drug discovery and proteomics/computing activities at Dundee were partially supported by Wellcome Trust strategic awards (nos. 100476/Z/12/Z, 094090/Z/10/Z and 097945/C/11/Z, respectively). We are thankful to D. Covini for synthesis support; G. Glendinning and S. Mayer for compound logistics; D. Haering and A. Weiss for help with cooperativity and protein degradation measurements; S. Winkler and M. Scharnweber for help with SPR measurements; K. Mayr for LogD measurements; S. Doebel, G. Flotzinger, G. Siszler and P. Werni for protein production and purification; P. Fyfe for support with the in-house X-ray facility; M. Gadd for the gift of the VHLR69A construct; D. Lamont for assistance in proteomics and V. Vetma for data analysis. We also thank the Diamond Light Source for beamtime (BAG proposal MX14980) and for beamline support at beamline IO4-1 and I24.",
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Farnaby, W, Koegl, M, Roy, MJ, 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, DB & Ciulli, A 2019, 'BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design', Nature Chemical Biology, vol. 15, no. 7, pp. 672-680. https://doi.org/10.1038/s41589-019-0294-6

BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. / Farnaby, William; Koegl, Manfred; Roy, Michael J.; Whitworth, Claire; Diers, Emelyne; Trainor, Nicole; Zollman, David; Steurer, Steffen; Karolyi-Oezguer, Jale; Riedmueller, Carina; Gmaschitz, Teresa; Wachter, Johannes; Dank, Christian; Galant, Michael; Sharps, Bernadette; Rumpel, Klaus; Traxler, Elisabeth; Gerstberger, Thomas; Schnitzer, Renate; Petermann, Oliver; Greb, Peter; Weinstabl, Harald; Bader, Gerd; Zoephel, Andreas; Weiss-Puxbaum, Alexander; Ehrenhöfer-Wölfer, Katharina; Wöhrle, Simon; Boehmelt, Guido; Rinnenthal, Joerg; Arnhof, Heribert; Wiechens, Nicola; Wu, Meng-Ying; Owen-Hughes, Tom; Ettmayer, Peter; Pearson, Mark; McConnell, Darryl B. (Lead / Corresponding author); Ciulli, Alessio (Lead / Corresponding author).

In: Nature Chemical Biology, Vol. 15, No. 7, 07.2019, p. 672-680.

Research output: Contribution to journalArticle

TY - JOUR

T1 - BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design

AU - Farnaby, William

AU - Koegl, Manfred

AU - Roy, Michael J.

AU - Whitworth, Claire

AU - Diers, Emelyne

AU - Trainor, Nicole

AU - Zollman, David

AU - Steurer, Steffen

AU - Karolyi-Oezguer, Jale

AU - Riedmueller, Carina

AU - Gmaschitz, Teresa

AU - Wachter, Johannes

AU - Dank, Christian

AU - Galant, Michael

AU - Sharps, Bernadette

AU - Rumpel, Klaus

AU - Traxler, Elisabeth

AU - Gerstberger, Thomas

AU - Schnitzer, Renate

AU - Petermann, Oliver

AU - Greb, Peter

AU - Weinstabl, Harald

AU - Bader, Gerd

AU - Zoephel, Andreas

AU - Weiss-Puxbaum, Alexander

AU - Ehrenhöfer-Wölfer, Katharina

AU - Wöhrle, Simon

AU - Boehmelt, Guido

AU - Rinnenthal, Joerg

AU - Arnhof, Heribert

AU - Wiechens, Nicola

AU - Wu, Meng-Ying

AU - Owen-Hughes, Tom

AU - Ettmayer, Peter

AU - Pearson, Mark

AU - McConnell, Darryl B.

AU - Ciulli, Alessio

N1 - partially supported by a European Research Council (ERC) Starting Grant (grant agreement no. ERC-2012-StG-311460 DrugE3CRLs). Biophysics, drug discovery and proteomics/computing activities at Dundee were partially supported by Wellcome Trust strategic awards (nos. 100476/Z/12/Z, 094090/Z/10/Z and 097945/C/11/Z, respectively). We are thankful to D. Covini for synthesis support; G. Glendinning and S. Mayer for compound logistics; D. Haering and A. Weiss for help with cooperativity and protein degradation measurements; S. Winkler and M. Scharnweber for help with SPR measurements; K. Mayr for LogD measurements; S. Doebel, G. Flotzinger, G. Siszler and P. Werni for protein production and purification; P. Fyfe for support with the in-house X-ray facility; M. Gadd for the gift of the VHLR69A construct; D. Lamont for assistance in proteomics and V. Vetma for data analysis. We also thank the Diamond Light Source for beamtime (BAG proposal MX14980) and for beamline support at beamline IO4-1 and I24.

PY - 2019/7

Y1 - 2019/7

N2 - 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.

AB - 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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DO - 10.1038/s41589-019-0294-6

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JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

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