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PDBsum entry 6pd9
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Transferase/transferase inhibitor
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PDB id
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6pd9
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References listed in PDB file
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Key reference
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Title
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Discovery of acylsulfonohydrazide-Derived inhibitors of the lysine acetyltransferase, Kat6a, As potent senescence-Inducing anti-Cancer agents.
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Authors
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D.L.Priebbenow,
D.J.Leaver,
N.Nguyen,
B.Cleary,
H.R.Lagiakos,
J.Sanchez,
L.Xue,
F.Huang,
Y.Sun,
P.Mujumdar,
R.Mudududdla,
S.Varghese,
S.Teguh,
S.A.Charman,
K.L.White,
D.M.Shackleford,
K.Katneni,
M.Cuellar,
J.M.Strasser,
J.L.Dahlin,
M.A.Walters,
I.P.Street,
B.J.Monahan,
K.E.Jarman,
H.Jousset sabroux,
H.Falk,
M.C.Chung,
S.J.Hermans,
N.L.Downer,
M.W.Parker,
A.K.Voss,
T.Thomas,
J.B.Baell.
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Ref.
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J Med Chem, 2020,
63,
4655-4684.
[DOI no: ]
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PubMed id
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Abstract
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A high-throughput screen designed to discover new inhibitors of histone
acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl
acylsulfonohydrazide with an IC50 of 1.0 μM. Using this
acylsulfonohydrazide as a template, we herein disclose the results of our
extensive structure-activity relationship investigations, which resulted in the
discovery of advanced compounds such as 55 and 80. These two
compounds represent significant improvements on our recently reported
prototypical lead WM-8014 (3) as they are not only equivalently potent as
inhibitors of KAT6A but are less lipophilic and significantly more stable to
microsomal degradation. Furthermore, during this process, we discovered a
distinct structural subclass that contains key 2-fluorobenzenesulfonyl and
phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This
compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM;
KD = 0.002 μM), competes with Ac-CoA by binding to the Ac-CoA
binding site, and has an oral bioavailability of 56% in rats.
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