Cresset, Enamine Extend Targeted Protein Degradation Collaboration

In a press release on Aug. 5, 2024, Cambridge, UK-based Cresset said it would be expanding its global collaboration with Enamine in the field of targeted protein degradation (TPD) (1). TPD is a research strategy which, Cresset said, boasts ever-expanding applications in both chemical probe and therapeutic agent development.

Proteolysis-targeting chimeras (PROTACs), which consist of a protein of interest (POI)-binding ligand and E3-ligase ligand joined by a linker, are a major class of small molecules commonly used for TPD, according to the press release (1,2). Cresset says that design of the linkers can be a challenge in terms of optimization when accounting for not only degradation, but also both physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties.

However, to assist in this process, Enamine has compiled a library of some 5400 TPD-related linkers, available worldwide, and designed 13,000 more linker molecules. The new extension of the partnership between Cresset and Enamine refers to the integration of the linker library into Cresset’s Spark, a bioisostere replacement tool that Cresset says has been widely used for hit and lead optimization (1).

Spark uses an extended electron distribution (XED) forcefield, along with a similarity scoring algorithm, to search libraries for fragments that have similar electrostatics and shape to the scaffold or R-group of interest. The tool’s ability to “scaffold hop” allows the user to treat the linker as the scaffold to be replaced with a bioisosterically similar fragment—but because databases rarely include degrader links due to both molecule size and flexibility, Enamine’s TPD-related library permits searching for known degrader linkers, larger and more flexible than fragments in previously existing libraries (1).

“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,” Mark Mackey, PhD, Cresset chief scientific officer, said in the release. “We are excited to continue working with Enamine to help our customers advance their projects by designing the best molecules they can.”

Cresset says early experiments have been very promising, an encouraging sign that the libraries put at users’ fingertips could prove very useful in the design of heterobifunctional molecules and molecule linkers used in TPD (1).

“We are happy to continue our productive collaboration with Cresset. Furthermore, providing streamlined access to (the) Enamine TPD-related linker library in Spark gives our joined customers a great solution for bioisosteric replacement and scaffold hopping,” said Vladimir Ivanov, PhD, Enamine executive vice president, in the press release. “Moreover, finding analogs to the linkers of interest is available via Enamine make-on-demand (MADE) building blocks, deliverable within four to six weeks, and via Enamine contract chemistry services.”

References

1. Cresset. Cresset Collaborates with Global Leaders Enamine to Enable the Design of Exciting New Targeted Protein Degraders. Press Release. Aug. 5, 2024.
2. Paiva, S.- L.; Crews, C. M. Targeted Protein Degradation: Elements of PROTAC Design. Curr. Opin. Chem. Biol. 2019, 50, 111–119. DOI: 10.1016/j.cbpa.2019.02.022