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Stereoselective Synthesis of Allele-Specific BET Inhibitors

submitted on 16.05.2020, 18:30 and posted on 18.05.2020, 12:22 by Adam Bond, Andrea Testa, Alessio Ciulli
Developing stereoselective synthetic routes that are efficient and cost-effective is important to allow easy access to biologically active molecules. Our previous syntheses of allele-selective bumped inhibitors of the Bromo and Extra-Terminal (BET) bromodomain 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 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 confirmed 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 inhibitor and a viable route that will facilitate wider access to this compound class.


Novel PROTAC-based chemical biology approaches to induced protein knockdown across the proteome

Medical Research Scotland

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BBSRC grant BB/J001201/2

European Research Council Starting Grant ERC-2012-StG-311460 DrugE3CRLs

Wellcome Trust strategic award 100476/Z/12/Z

Wellcome Trust strategic award 094090/Z/10/Z


Email Address of Submitting Author


University of Dundee


United Kingdom

ORCID For Submitting Author


Declaration of Conflict of Interest

The authors declare the following competing financial interest(s): The Ciulli laboratory receives or has received sponsored research support from Boehringer Ingelheim, Eisai, Nurix, Ono Pharmaceuticals, and Amphista Therapeutics. A.C. is a scientific founder, shareholder, non-executive director and consultant of Amphista Therapeutics, a company that is developing targeted protein degradation therapeutic platforms. The remaining author reports no competing interests.

Version Notes

version 1, 16 May 2020