• Media type: E-Article
  • Title: Abstract 3849: Structure-based PROTAC design demonstrates BAF complex ATPase vulnerabilities in cancer
  • Contributor: Koegl, Manfred; Farnaby, William; Whitworth, Claire; Roy, Michael; Diers, Emelyne; Trainor, Nicole; Steurer, Steffen; Riedmueller, Carina; Gmaschitz, Teresa; Wachter, Johannes; Dank, Christian; Gallant, Michael; Sharps, Bernadette; Rumpel, Klaus; Traxler, Elisabeth; Lorenz, Romario; Petermann, Oliver; Greb, Peter; Weinstabl, Harald; Bader, Gerd; Zoephel, Andreas; Weiss-Puxbaum, Alexander; Rinnenthal, Joerg; Arnnhof, Heribert; [...]
  • Published in: Cancer Research
  • Published: American Association for Cancer Research (AACR), 2019
  • Language: English
  • DOI: 10.1158/1538-7445.am2019-3849
  • ISSN: 0008-5472; 1538-7445
  • Keywords: Cancer Research ; Oncology
  • Abstract: <jats:title>Abstract</jats:title> <jats:p>Targeting subunits of BAF/PBAF complexes has been proposed as an approach to exploit cancer vulnerabilities, yet small molecules developed to date have remained largely ineffectual. Here we develop 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 the rational optimization of ACBI1, a potent cooperative SMARCA2/4 degrader. ACBI1 induced antiproliferative 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 driven campaign to degrade targets previously considered undruggable, and pave the way towards new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.</jats:p> <jats:p>Citation Format: Manfred Koegl, William Farnaby, Claire Whitworth, Michael Roy, Emelyne Diers, Nicole Trainor, Steffen Steurer, Carina Riedmueller, Teresa Gmaschitz, Johannes Wachter, Christian Dank, Michael Gallant, Bernadette Sharps, Klaus Rumpel, Elisabeth Traxler, Romario Lorenz, Oliver Petermann, Peter Greb, Harald Weinstabl, Gerd Bader, Andreas Zoephel, Alexander Weiss-Puxbaum, Joerg Rinnenthal, Heribert Arnnhof, Nicola Wiechens, Meng-Ying Wu, Tom Owen-Hughes, Peter Ettmayer, Mark Pearson, Darryl B. McConnell, Alessio Ciulli. Structure-based PROTAC design demonstrates BAF complex ATPase vulnerabilities in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3849.</jats:p>
  • Description: <jats:title>Abstract</jats:title>
    <jats:p>Targeting subunits of BAF/PBAF complexes has been proposed as an approach to exploit cancer vulnerabilities, yet small molecules developed to date have remained largely ineffectual. Here we develop 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 the rational optimization of ACBI1, a potent cooperative SMARCA2/4 degrader. ACBI1 induced antiproliferative 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 driven campaign to degrade targets previously considered undruggable, and pave the way towards new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.</jats:p>
    <jats:p>Citation Format: Manfred Koegl, William Farnaby, Claire Whitworth, Michael Roy, Emelyne Diers, Nicole Trainor, Steffen Steurer, Carina Riedmueller, Teresa Gmaschitz, Johannes Wachter, Christian Dank, Michael Gallant, Bernadette Sharps, Klaus Rumpel, Elisabeth Traxler, Romario Lorenz, Oliver Petermann, Peter Greb, Harald Weinstabl, Gerd Bader, Andreas Zoephel, Alexander Weiss-Puxbaum, Joerg Rinnenthal, Heribert Arnnhof, Nicola Wiechens, Meng-Ying Wu, Tom Owen-Hughes, Peter Ettmayer, Mark Pearson, Darryl B. McConnell, Alessio Ciulli. Structure-based PROTAC design demonstrates BAF complex ATPase vulnerabilities in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3849.</jats:p>
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  • Access State: Open Access