05 August 2024 – Cambridge, UK – Cresset, an innovative provider of integrated in silico solutions for drug discovery, announces an extension of the global collaboration with Enamine, the world’s leading chemical and biological contract research organization and producer of novel building blocks for drug design, in the area of targeted protein degradation (TPD). 

TPD is an exciting research strategy with expanding applications in chemical probe and therapeutic agent development. A major class of small molecules commonly used for TPD are known as proteolysis-targeting chimeras (PROTACs), which consist of a POI-binding ligand and an E3-ligase ligand joined by a linker. Design of the linkers can be incredibly challenging in terms of optimization of both degradation and physicochemical and ADME properties. 

Enamine has synthesized a library of 5,400 TPD-related linkers, which are now available for prompt delivery worldwide, and designed a further 13,000 linker molecules available through quick synthesis. In response to customer requests, the Enamine Linker Library was deployed in Cresset’s Spark – a bioisostere replacement tool widely used for hit and lead optimization.  It uses the XED forcefield to search libraries for fragments with similar electrostatics and shape to the scaffold or R-group of interest using a similarity scoring algorithm. Spark is particularly valuable for designing heterobifunctional molecules used in TPD.

With Spark scaffold hopping, the user may treat the linker as the scaffold to be replaced with a bioisosterically similar fragment from the readily available databases. However, these databases rarely include degrader linkers due to their molecular size and flexibility.

Integration of the new Enamine TPD-related Linker Library in Spark enables searching for known degrader linkers, which are usually larger and more flexible than typical fragments found in existing libraries. Early experiments show very promising results, suggesting these libraries could be key in designing heterobifunctional molecule linkers.

Commenting on the latest collaboration, Dr Vladimir Ivanov, Enamine’s Executive Vice President said, “We are happy to continue our productive collaboration with Cresset. Furthermore, providing streamlined access to Enamine TPD-related Linker Library in Spark gives our joined customers a great solution for bioisosteric replacement and scaffold hopping. Moreover, finding analogs to the linkers of interest is available via Enamine MADE building blocks, deliverable within 4-6 weeks, and via Enamine contract chemistry services.”

Cresset’s Chief Scientific Officer, Dr Mark Mackey commented, “Spark is the industry's favourite bioisostere replacement tool, and the addition of these linker libraries will expand the utility of Spark to an even wider set of small molecule drug discovery programs. We are excited to continue working with Enamine to help our customers advance their projects by designing the best molecules they can.”

A further collaborative webinar will take place in September, more details of which will be announced in due course.

For more information about the collaborators visit www.cresset-group.com and www.enamine.net.