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BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design
DOI:
10.1038/s41589-019-0294-6
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
Added On:
18/06/2019 14:14
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Chemistry
Structural biology
Biophysics
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)