{"id":2285,"date":"2020-08-05T10:18:00","date_gmt":"2020-08-05T09:18:00","guid":{"rendered":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/?p=2285"},"modified":"2026-01-26T16:28:03","modified_gmt":"2026-01-26T16:28:03","slug":"stereoselective-syntheses-of-allele-selective-bet-inhibitors-bumped-jq1","status":"publish","type":"post","link":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/2020\/08\/05\/stereoselective-syntheses-of-allele-selective-bet-inhibitors-bumped-jq1\/","title":{"rendered":"Stereoselective syntheses of allele-selective BET inhibitors bumped-JQ1"},"content":{"rendered":"

Our new paper describing stereoselective syntheses of allele-selective BET inhibitors bumped-JQ1 is now out in the RSC journal Org. Biomol. Chem.<\/p>\n

Congratulations to Adam and Andrea, on their development of this new route to synthesise the compounds!\u00a0\u00a0<\/p>\n

Read the Open Access full article<\/a>.<\/p>\n

Authors<\/strong>: Adam G. Bond, Andrea Testa and Alessio Ciulli*<\/p>\n

Title<\/strong>: Stereoselective synthesis of allele-specific BET inhibitors<\/p>\n

Abstract<\/strong><\/h2>\n

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.<\/p>\n