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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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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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Crystal structure of myst acetyltransferase domain in complex with inhibitor 60
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Structure:
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Histone acetyltransferase kat8. Chain: a. Synonym: lysine acetyltransferase 8,moz,ybf2/sas3,sas2 and tip60 protein 1,hmof. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: kat8, mof, myst1, pp7073. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.80Å
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R-factor:
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0.215
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R-free:
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0.267
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Authors:
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S.J.Hermans,M.W.Parker,T.Thomas,J.B.Baell
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Key ref:
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D.L.Priebbenow
et al.
(2020).
Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents.
J Med Chem,
63,
4655-4684.
PubMed id:
DOI:
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Date:
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18-Jun-19
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Release date:
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01-Apr-20
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PROCHECK
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Headers
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References
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Q9H7Z6
(KAT8_HUMAN) -
Histone acetyltransferase KAT8 from Homo sapiens
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Seq:
Struc:
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458 a.a.
268 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 8 residue positions (black
crosses)
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Enzyme class 1:
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E.C.2.3.1.-
- ?????
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Enzyme class 2:
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E.C.2.3.1.48
- histone acetyltransferase.
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Reaction:
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L-lysyl-[protein] + acetyl-CoA = N6-acetyl-L-lysyl-[protein] + CoA + H+
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L-lysyl-[protein]
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+
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acetyl-CoA
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=
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N(6)-acetyl-L-lysyl-[protein]
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+
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CoA
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+
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H(+)
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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
63:4655-4684
(2020)
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PubMed id:
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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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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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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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