6YTM

Human Brd2(BD2) L383V mutant in complex with ET-JQ1-OMe

Summary for 6YTM

• Entry DOI: 10.2210/pdb6ytm/pdb
• Descriptor: Bromodomain-containing protein 2, methyl (2R)-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,7,10,12-pentaen-9-yl]butanoate, (2S)-1-[3-{[(2R)-2-hydroxypropyl]oxy}-2,2-bis({[(2R)-2-hydroxypropyl]oxy}methyl)propoxy]propan-2-ol, ... (4 entities in total)
• Functional Keywords: epigenetics, bump and hole, brd2, second bromodomain, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 28345.62

Authors

Bond, A.G.,Ciulli, A.,Cowan, A.D. (deposition date: 2020-04-24, release date: 2020-05-27, Last modification date: 2024-01-24)

Primary citation

Bond, A.G.,Testa, A.,Ciulli, A.
Stereoselective synthesis of allele-specific BET inhibitors.
Org.Biomol.Chem., 18:7533-7539, 2020

PubMed Abstract: Developing stereoselective synthetic routes that are efficient and cost-effective allows easy access to biologically active molecules. Our previous syntheses of allele-selective bumped inhibitors of the Bromo and Extra-Terminal (BET) domain proteins, Brd2, Brd3, Brd4 and BrdT, required a wasteful, late-stage alkylation step and expensive chiral separation. To circumvent these limitations, we developed a route based on stereocontrolled alkylation of an N-Pf protected aspartic acid derivative that was used in a divergent, racemisation-free protocol to yield structurally diverse and enantiopure triazolodiazepines. With this approach, we synthesized bumped thienodiazepine-based BET inhibitor, ET-JQ1-OMe, in five steps and 99% ee without the need for chiral chromatography. Exquisite selectivity of ET-JQ1-OMe for Leu-Ala and Leu-Val mutants over wild-type bromodomain was established by isothermal titration calorimetry and X-ray crystallography. Our new approach provides unambiguous chemical evidence for the absolute stereochemistry of the active, allele-specific BET inhibitors and a viable route that will open wider access to this compound class.

PubMed: 32756710
DOI: 10.1039/d0ob01165g

Experimental method

X-RAY DIFFRACTION (1.56 Å)