Stereoselective synthesis of allele-specific BET inhibitors

Adam Bond, Andrea Testa, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
34 Downloads (Pure)


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.

Original languageEnglish
Pages (from-to)7533-7539
Number of pages7
JournalOrganic and Biomolecular Chemistry
Issue number38
Early online date5 Aug 2020
Publication statusPublished - 14 Oct 2020


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