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

  • ToC graphics
  • Figure 1. Pan and allele-selective BET inhibitors.
  • Figure 2 Synthetic routes to bumped BET inhibitors.
  • Scheme 1 Stereoselective synthesis of N-carboxyanhydrides 10 and 11.
  • Scheme 2 Formation of thienodiazepines 15–18 and benzodiazepine derivatives 22 and 23.
  • Fig. 3 Biophysical and structural characterization of novel JQ1-based bumped inhibitor.

Congratulations to Adam and Andrea, on their development of this new route to synthesise the compounds!  

Read the Open Access full article here.

Authors: Adam G. Bond, Andrea Testa and Alessio Ciulli*

Title: 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.