Photoaffinity labeling (PAL) is a successful and widespread strategy for ligand-binding site mapping, protein target-fishing, and target identification with affinity-based probes (AfBP). Medicinal chemists and structural biologists often use this powerful technique to reveal molecular targets after phenotypic screens and investigate signaling pathways and interactions between proteins of interest. PAL has become one of the most used tools in chemical proteomics and the studies of protein-protein interactions (PPIs).

Diazirines, benzophenones, and aryl azides are traditional, well-described photocrosslinkers (PLs) used in PAL. Upon photoirradiation, these moieties produce highly reactive species that quickly react with adjacent protein parts resulting in covalent binding, which can be further identified by mass-spec analysis and other methods. We at Enamine have been working on synthesizing new PLs containing molecules for years and now offer the largest and most diverse source of Photoaffinity Compounds, including a vast collection of Fully Functionalized Compounds.

Cereblon (CRBN) is one of the most explored E3 ligases extensively used to construct PROTACs, search for new Molecular Glues, and develop functionalized tool compounds. The most extensive research has been done in this area. CRBN ligands are also known to have a good ADME profile, allowing for the development of orally bioavailable PROTACs.

We have been working with Thalidomide-like and Glutarimide chemistry for years and gained versatile experience in this chemistry field. Our experienced chemists are continuously working on the design and synthesis of new attractive Building Blocks, while our parallel chemistry group extensively elaborates approaches in the modification of the most interesting intermediates. This knowledge allowed us to enumerate a REAL Array of over 18 million CRBN-focused compounds, which can be synthesized within only 4 weeks and with 80% success rate.

For a long time, Indisulam and a few other clinically tested aryl sulfonamides such as Tasisulam and chloroquinoxaline sulfonamide (CQS) remained compounds with pronounced selective in vitro anticancer activity and unclear action mechanisms. Recent extensive investigations in cancer genome sequencing together with X-Ray crystallography and cryo-EM showed that these compounds act as a “molecular glue” to induce degradation of RBM39 via complex formation and recruiting CUL-4-DCAF15 E3 ligase. This insight provided structural and mechanistic data that significantly extended our understanding of their mode of action. Further research in this area reveals covalent binders of other members of DCAF family proteins, such as DCAF1, DCAF11, and DCAF16.

Recent structural data and reported DCAF binders allowed us to design a dedicated library of compounds with the potential to act as molecular glues. The library is now available in a pre-plated format and can be quickly delivered in any convenient for your project format.

The recently emerged therapeutic area that modulates the ubiquitin-proteasome system needs new and reliable chemistry. Booming biological assays in this field of drug discovery require the production of hundreds and thousands of new functional intermediates, bifunctional molecules, and new molecular glues. The time needed to produce new derivatives is crucial at any stage of the drug discovery program. We offer advanced synthetic chemistry support, including custom library design and synthesis.