5EK9

Crystal structure of the second bromodomain of human BRD2 in complex with a tetrahydroquinoline inhibitor

Summary for 5EK9

• Entry DOI: 10.2210/pdb5ek9/pdb
• Descriptor: Bromodomain-containing protein 2, propan-2-yl ~{N}-[(2~{S},4~{R})-1-ethanoyl-6-(furan-2-yl)-2-methyl-3,4-dihydro-2~{H}-quinolin-4-yl]carbamate (3 entities in total)
• Functional Keywords: chromatin and transcription regulator, acetylation, structural genomics, structural genomics consortium, sgc, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P25440
• Total number of polymer chains: 2
• Total formula weight: 27463.65

Authors

Tallant, C.,Slavish, P.J.,Siejka, P.,Bharatham, N.,Shadrick, W.R.,Chai, S.,Young, B.M.,Boyd, V.A.,Heroven, C.,Picaud, S.,Fedorov, O.,Chen, T.,Lee, R.E.,Guy, R.K.,Shelat, A.A.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2015-11-03, release date: 2016-11-16, Last modification date: 2024-05-08)

Primary citation

Shadrick, W.R.,Slavish, P.J.,Chai, S.C.,Waddell, B.,Connelly, M.,Low, J.A.,Tallant, C.,Young, B.M.,Bharatham, N.,Knapp, S.,Boyd, V.A.,Morfouace, M.,Roussel, M.F.,Chen, T.,Lee, R.E.,Kiplin Guy, R.,Shelat, A.A.,Potter, P.M.
Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors.
Bioorg. Med. Chem., 26:25-36, 2018

PubMed 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 EC values comparable to BET inhibitor (BETi) clinical candidates.

PubMed: 29170024
DOI: 10.1016/j.bmc.2017.10.042

Experimental method

X-RAY DIFFRACTION (2.08 Å)