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PDBsum entry 6hax
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Gene regulation
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PDB id
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6hax
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Contents |
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115 a.a.
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149 a.a.
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88 a.a.
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104 a.a.
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121 a.a.
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97 a.a.
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References listed in PDB file
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Key reference
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Title
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Baf complex vulnerabilities in cancer demonstrated via structure-Based protac design.
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Authors
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W.Farnaby,
M.Koegl,
M.J.Roy,
C.Whitworth,
E.Diers,
N.Trainor,
D.Zollman,
S.Steurer,
J.Karolyi-Oezguer,
C.Riedmueller,
T.Gmaschitz,
J.Wachter,
C.Dank,
M.Galant,
B.Sharps,
K.Rumpel,
E.Traxler,
T.Gerstberger,
R.Schnitzer,
O.Petermann,
P.Greb,
H.Weinstabl,
G.Bader,
A.Zoephel,
A.Weiss-Puxbaum,
K.Ehrenhöfer-Wölfer,
S.Wöhrle,
G.Boehmelt,
J.Rinnenthal,
H.Arnhof,
N.Wiechens,
M.Y.Wu,
T.Owen-Hughes,
P.Ettmayer,
M.Pearson,
D.B.Mcconnell,
A.Ciulli.
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Ref.
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Nat Chem Biol, 2019,
15,
672-680.
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PubMed id
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Abstract
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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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