Stereoselective Synthesis of Allele-Specific BET Inhibitors

18 May 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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.

Keywords

stereoselective synthesis route
stereoselective synthesis
stereoselective synthesis strategy
BET inhibitors
bump-hole engineering
bromodomains
selectivity
chemical probes

Supplementary materials

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