Cresset Collaborates With Enamine to Enable the Design of Exciting New Targeted Protein Degraders

Cresset recently announced 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, added “Spark is the industry’s favorite 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.”

Chemists in the world’s leading research organizations use Cresset solutions to discover, design, optimize, synthesize and track the best small molecules. Our patented CADD Software, collaborative Torx^® DMTA design-make-test-analyze platform, and expert Discovery CRO scientists, enable chemists to enhance efficiency and win the race to scientific success in industry sectors including pharmaceuticals, agrochemicals, fine chemicals and flavors and fragrances.  www.cresset-group.com

Enamine is a scientifically driven integrated discovery Contract Research Organization with unique partnering opportunities in exploring new chemical space. The company combines access to the in-house produced screening compounds (4.2M in stock) and building blocks (300K in stock) with a comprehensive platform of integrated discovery services to advance and accelerate the efforts in Drug Discovery. For more information, visit https://enamine.net.

Enamine MADE (MAke-on-DEmand) building blocks are a catalog of 1 billion chemical building blocks that can be synthesized within several weeks using short pre-validated experience and starting materials from Enamine stock in 2-4 steps with a 75% success rate. For more information, visit https://enamine.net/building-blocks/made-building-blocks.

Enamine Fast MADE building blocks is a special set of Enamine MADE building blocks. The Fast MADE catalog contains 78.7 million molecules that can be synthesized in ultra-short terms (within 7 to 10 days), through 1-3 commonly utilized procedures with an 80% success rate. For more information, visit https://enamine.net/building-blocks/fast-made-building-blocks.