Issue 38, 2020

Stereoselective synthesis of allele-specific BET inhibitors


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.

Graphical abstract: Stereoselective synthesis of allele-specific BET inhibitors

Supplementary files

Article information

Article type
05 Jun 2020
09 Jul 2020
First published
05 Aug 2020
This article is Open Access
Creative Commons BY license

Org. Biomol. Chem., 2020,18, 7533-7539

Stereoselective synthesis of allele-specific BET inhibitors

A. G. Bond, A. Testa and A. Ciulli, Org. Biomol. Chem., 2020, 18, 7533 DOI: 10.1039/D0OB01165G

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