CELMoDs library
ChemDiv’s library of Cereblon E3 Ligase Modulation Drugs (CELMoDs) contains more than 25,000 compounds.
Our CELMoDs library represents a revolutionary step in the area of targeted protein degradation, building upon the foundations laid by IMiDs, PROTACs, and molecular glue technologies. These molecular glue compounds are designed to manipulate the cereblon (CRBN) protein conformation, enhancing its ability to mediate the proteasomal degradation of specific target proteins. This is achieved through the stabilization of CRBN in its closed conformation, wherein the thalidomide binding domain (TBD) and Lon protease-like domain (Lon) are brought into proximity. This proximity is crucial as it facilitates the binding and subsequent degradation of the target protein, a mechanism that has been exemplified by compounds such as CC-92480 (mezigdomide) and CC-220 (Iberdomide), which interact beneficially with the sensor loop of CRBN.
Our specialized library of ChemDiv compounds has been curated, characterized by their potential to stabilize CRBN's closed conformation, to aid in the discovery and development of new CELMoDs. This library not only accelerates the identification of novel molecular glues but also enriches the arsenal of tools available for manipulating protein degradation pathways. Through advanced molecular docking techniques, compounds within this library have been screened for high ligand efficiency, indicating a strong propensity to occupy the thalidomide binding pocket effectively. This dual functionality makes the CELMoDs library a versatile resource for drug discovery, offering compounds that can act both as direct molecular glues and as novel warheads for CRBN targeting. Researchers can leverage this library for direct screening of potential molecular glues, sourcing alternative warheads, and deriving medicinal chemistry insights for both existing and novel CRBN modulation strategies, thereby expanding the scope of targeted degradation therapies and opening new avenues for therapeutic intervention.
Our CELMoDs library offers several unique characteristics that distinguish it from existing analog libraries used in drug discovery, particularly those focused on targeted protein degradation and molecular glue technologies. Unlike general small molecule or PROTAC libraries, the CELMoDs library is specifically curated to influence the CRBN protein, targeting its closed conformation. This precise focus allows for the selective stabilization of the CRBN complex in a state that is more conducive to binding and degrading target proteins, a mechanism that is not generally addressed by broader libraries.
The compounds in the CELMoDs library are selected based on their ability to promote the enhanced degradation activity of CRBN. This is achieved through favorable interactions with CRBN's sensor loop, which is a less common target in traditional molecular glue or PROTAC libraries that typically focus on binding efficacy without necessarily enhancing the protein's natural degradation pathway.
Our library contains dual functioning compounds that not only act as effective molecular glues by stabilizing the CRBN in its functional conformation but also have high predicted ligand efficiency for occupying the thalidomide binding pocket. This dual functionality is particularly advantageous as it allows for the exploration of compounds that can serve multiple roles in drug development, including acting as direct inhibitors or as scaffolds for further PROTAC development.
The CELMoDs library is designed not just to supply active compounds but also to provide valuable medicinal chemistry insights. It serves as a source of innovative ideas for both targeting the CRBN protein and designing new warheads. This aspect is crucial for advancing the field of targeted protein degradation, offering a rich resource for hypothesis testing and novel drug design strategies. Compounds within this library have been pre-screened using molecular docking to identify those with high ligand efficiency, ensuring a high-quality starting point for further development. This pre-screening saves considerable time and resources in early drug discovery phases and increases the chances of success in later stages.
This is a unique and powerful toolkit for researchers focused on developing new therapies through the mechanism of targeted protein degradation. Its specialized and multifunctional approach makes it a superior choice compared to more generic libraries, enabling more efficient and effective drug discovery and development processes.