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Bioorg Med Chem. 2018 Jan 1;26(1):25-36. doi: 10.1016/j.bmc.2017.10.042. Epub 2017 Nov 4.

Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors.

Author information

1
Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
2
Molecular Interaction Analysis Shared Resource, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
3
Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford OX3 7FZ, UK; Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
4
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
5
Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. Electronic address: anang.shelat@stjude.org.

Abstract

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 EC50 values comparable to BET inhibitor (BETi) clinical candidates.

PMID:
29170024
PMCID:
PMC5733700
[Available on 2019-01-01]
DOI:
10.1016/j.bmc.2017.10.042
[Indexed for MEDLINE]

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