Efficient, multi-hundred-gram scale access to E3 ubiquitin ligase ligands for degrader development.

Small molecule heterobifunctional degraders (commonly also known as PROTACs) offer tremendous potential to deliver new therapeutics in areas of unmet medical need. To deliver on this promise, a new discipline directed at degrader design and optimization has emerged within medicinal chemistry to address a central challenge, namely how to optimize relatively large, heterobifunctional molecules for activity, whilst maintaining drug-like properties. This process involves simultaneous optimization of the three principle degrader components: E3 ubiquitin ligase ligand, linker, and protein of interest (POI) ligand.

A Convenient, Rapid, Conventional Heating Route to MIDA Boronates.

A cheap, conventional, sealed heating reactor proved to be a useful alternative to a microwave reactor in the synthesis of a >20-member MIDA boronate library (MIDA = N-methyliminodiacetic acid). Reaction times were 10 min and work-ups were minimal, saving on energy and solvent usage.

Scale-up and optimization of the synthesis of dual CBP/BRD4 inhibitor ISOX-DUAL.

ISOX-DUAL is a dual inhibitor of CBP/p300 (IC = 0.65 μM) and BRD4 (IC = 1.5 μM) bromodomains, and a useful chemical probe for epigenetic research.