Cresset and Enamine extend their collaboration in targeted protein degradation
Enamine's library of 5400 TPD-related linkers, as well as 13,000 additional linker molecules, is now integrated into Cresset's Spark library search tool
Cambridge, UK-based Cresset announced on Aug. 5, 2024, that it plans to enhance its global collaboration with Enamine in the area of targeted protein degradation (TPD) (1). TPD is a research strategy that Cresset claims has a wide range of applications in the development of chemical probes and therapeutic agents.
Proteolysis-targeting chimeras (PROTACs) are widely used in the field of targeted protein degradation (TPD). These small molecules are composed of a protein of interest (POI)-binding ligand and an E3-ligase ligand connected by a linker. The press release highlights the significance of PROTACs in this area. Cresset explains that optimizing the design of linkers can be a complex task, as it involves considering factors such as degradation, physicochemical properties, and absorption, distribution, metabolism, and excretion (ADME) properties.
Enamine has created a library of over 5,400 TPD-related linkers that are accessible globally. Additionally, they have developed an impressive 13,000 more linker molecules to aid in this process. Cresset and Enamine have recently expanded their partnership by integrating the linker library into Cresset's Spark. Spark is a bioisostere replacement tool that Cresset claims has been extensively utilized for hit and lead optimization.
Spark utilizes an extended electron distribution (XED) forcefield and a similarity scoring algorithm to explore libraries for fragments that exhibit comparable electrostatics and shape to the scaffold or R-group of interest. The tool's unique feature of "scaffold hopping" enables users to replace the linker with a bioisosterically similar fragment. However, most databases do not contain degrader links due to their size and flexibility. Enamine's TPD-related library overcomes this limitation by allowing users to search for known degrader linkers that are larger and more flexible than the fragments found in other libraries.
According to Mark Mackey, PhD, the chief scientific officer at Cresset, the inclusion of these linker libraries will further enhance the versatility of Spark, the highly regarded bioisostere replacement tool in the industry. This development will benefit a broader range of small-molecule drug discovery programs. "We are thrilled to continue our collaboration with Enamine in order to assist our customers in making significant progress in their projects by creating highly effective molecules."
Cresset reports that initial experiments have shown great promise, indicating that the accessible libraries could be highly valuable in the development of heterobifunctional molecules and molecule linkers used in TPD.
We are pleased to maintain our successful partnership with Cresset. In addition, Dr. Vladimir Ivanov, Enamine's executive vice president, highlighted the benefits of offering easy access to the Enamine TPD-related linker library in Spark. This solution provides our customers with a valuable tool for bioisosteric replacement and scaffold hopping, as mentioned in the press release. Furthermore, Enamine offers the option to find analogs to the linkers of interest through their Enamine make-on-demand (MADE) building blocks. These building blocks can be delivered within four to six weeks. Enamine also provides contract chemistry services for this purpose.
Source: Cresset, Science Direct
