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

DOI: 10.1038/s41589-019-0294-6 DOI Help

Authors: William Farnaby (University of Dundee) , Manfred Koegl (Boehringer Ingelheim RCV GmbH & Co KG) , Michael J. Roy (University of Dundee) , Claire Whitworth (University of Dundee) , Emelyne Diers (University of Dundee) , Nicole Trainor (University of Dundee) , David Zollman (University of Dundee) , Steffen Steurer (Boehringer Ingelheim RCV GmbH & Co KG) , Jale Karolyi-oezguer (Boehringer Ingelheim RCV GmbH & Co KG) , Carina Riedmueller (Boehringer Ingelheim RCV GmbH & Co KG) , Teresa Gmaschitz (Boehringer Ingelheim RCV GmbH & Co KG) , Johannes Wachter (Boehringer Ingelheim RCV GmbH & Co KG) , Christian Dank (Boehringer Ingelheim RCV GmbH & Co KG) , Michael Galant (Boehringer Ingelheim RCV GmbH & Co KG) , Bernadette Sharps (Boehringer Ingelheim RCV GmbH & Co KG) , Klaus Rumpel (Boehringer Ingelheim RCV GmbH & Co KG) , Elisabeth Traxler (Boehringer Ingelheim RCV GmbH & Co KG) , Thomas Gerstberger (Boehringer Ingelheim RCV GmbH & Co KG) , Renate Schnitzer (Boehringer Ingelheim RCV GmbH & Co KG) , Oliver Petermann (Boehringer Ingelheim RCV GmbH & Co KG) , Peter Greb (Boehringer Ingelheim RCV GmbH & Co KG) , Harald Weinstabl (Boehringer Ingelheim RCV GmbH & Co KG) , Gerd Bader (Boehringer Ingelheim RCV GmbH & Co KG) , Andreas Zoephel (Boehringer Ingelheim RCV GmbH & Co KG) , Alexander Weiss-puxbaum (Boehringer Ingelheim RCV GmbH & Co KG) , Katharina Ehrenhöfer-wölfer (Boehringer Ingelheim RCV GmbH & Co KG) , Simon Wöhrle (Boehringer Ingelheim RCV GmbH & Co KG) , Guido Boehmelt (Boehringer Ingelheim RCV GmbH & Co KG) , Joerg Rinnenthal (Boehringer Ingelheim RCV GmbH & Co KG) , Heribert Arnhof (Boehringer Ingelheim RCV GmbH & Co KG) , Nicola Wiechens (University of Dundee) , Meng-ying Wu (University of Dundee) , Tom Owen-hughes (University of Dundee) , Peter Ettmayer (Boehringer Ingelheim RCV GmbH & Co KG) , Mark Pearson (Boehringer Ingelheim RCV GmbH & Co KG) , Darryl B. Mcconnell (Boehringer Ingelheim RCV GmbH & Co KG) , Alessio Ciulli (University of Dundee)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature Chemical Biology

State: Published (Approved)
Published: June 2019
Diamond Proposal Number(s): 14980

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.

Journal Keywords: Cancer therapy; Chemical tools; Drug discovery; Structure-based drug design

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography