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PDBsum entry 5ek9
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Transcription
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PDB id
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5ek9
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References listed in PDB file
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Key reference
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Title
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Exploiting a water network to achieve enthalpy-Driven, Bromodomain-Selective bet inhibitors.
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Authors
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W.R.Shadrick,
P.J.Slavish,
S.C.Chai,
B.Waddell,
M.Connelly,
J.A.Low,
C.Tallant,
B.M.Young,
N.Bharatham,
S.Knapp,
V.A.Boyd,
M.Morfouace,
M.F.Roussel,
T.Chen,
R.E.Lee,
R.Kiplin guy,
A.A.Shelat,
P.M.Potter.
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Ref.
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Bioorg Med Chem, 2018,
26,
25-36.
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PubMed id
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Abstract
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Within the last decade, the Bromodomain and Extra-Terminal domain family (BET)
of proteins have emerged as promising drug targets in diverse clinical
indications including oncology, auto-immune disease, heart failure, and male
contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and
BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains
(BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and
appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at
five positions near the substrate binding pocket: the variation in the ZA
channel induces different water networks nearby. We designed a set of congeneric
2- and 3-heteroaryl substituted tetrahydroquinolines (THQ) to differentially
engage bound waters in the ZA channel with the goal of achieving bromodomain
selectivity. SJ830599 (9) showed modest, but consistent, selectivity for
BRD2-BD2. Using isothermal titration calorimetry, we showed that the binding of
all THQ analogs in our study to either of the two bromodomains was enthalpy
driven. Remarkably, the binding of 9 to BRD2-BD2 was marked by negative entropy
and was entirely driven by enthalpy, consistent with significant restriction of
conformational flexibility and/or engagement with bound waters.
Co-crystallography studies confirmed that 9 did indeed stabilize a
water-mediated hydrogen bond network. Finally, we report that 9 retained
cytotoxicity against several pediatric cancer cell lines with
EC50values comparable to BET inhibitor (BETi) clinical candidates.
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