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.

Chirality: a key parameter in chemical probes.

Many small molecule bioactive and marketed drugs are chiral. They are often synthesised from commercially available chiral building blocks. However, chirality is sometimes incorrectly assigned by manufacturers with consequences for the end user ranging from: experimental irreproducibility, wasted time on synthesising the wrong product and reanalysis, to the added cost of purchasing the precursor and resynthesis of the correct stereoisomer.

Diastereomeric Resolution Yields Highly Potent Inhibitor of SARS-CoV-2 Main Protease.

SARS-CoV-2 is the causative agent behind the COVID-19 pandemic. The main protease (M, 3CL) of SARS-CoV-2 is a key enzyme that processes polyproteins translated from the viral RNA. M is therefore an attractive target for the design of inhibitors that block viral replication.

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.

Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma.

CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric sarcoma driven by a fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to the C-terminal transcriptional activation domain of DUX4. CDS rapidly develops resistance to chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that CIC-DUX4 requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis.

Reviewing the toolbox for degrader development in oncology.

The field of targeted protein degradation encompasses a growing number of modalities that achieve potent and selective knockdown of target proteins at the post-translational level. Among the most clinically advanced are bifunctional small-molecule degraders, also referred to as PROteolysis Targeting Chimeras, Degronimids, SNIPERs, or uSMITEs. Although applicable to many disease indications, oncology stands to be the first to benefit from this promising therapeutic approach, with the first investigational new drugs (INDs) filed in 2019 and a proliferation of research specifically focused on harnessing degraders for cancer treatment.

An efficient synthesis of nitroalkenes by alkene cross metathesis: facile access to small ring systems.

A synthesis of highly functionalized nitroalkenes is reported that utilizes a cross metathesis (CM) reaction between simple aliphatic nitro compounds and a range of substituted alkenes. This chemistry offers a simple and attractive route to nitroalkenes that would otherwise be difficult to prepare, and that have a very useful application as precursors to a variety of heterocyclic entities.