IMiD small molecule library

ChemDiv’s collection of imide-like compounds for the discovery of PROTAC and molecular glue molecules contains 2,000 entries.

Imide-like compounds provide the scientific background for discovering and developing PROTACs and molecular glue drug compounds, two innovative strategies in targeted protein degradation. These compounds act as crucial connectors or "glues" that facilitate the interaction between target proteins and the cellular degradation machinery via engagement with E3 ligase.

Imide-like compounds, such as thalidomide and its derivatives (lenalidomide and pomalidomide), have been found to bind to the E3 ligase, serving as the E3 ligase-recruiting moiety in PROTAC molecules. By facilitating the recruitment of E3 ligases, imide-like compounds enable the selective degradation of pathogenic proteins, offering a highly specific approach to drug development, particularly for diseases like cancer where certain proteins are aberrantly overexpressed. Those compounds have been instrumental in the discovery of molecular glue drugs because of their ability to induce neo-interactions between the E3 ligase and the target protein that do not occur naturally. For instance, thalidomide and its analogs bind to the E3 ubiquitin ligase cereblon, changing which substrates it binds to and "gluing" itself to new ones. These new substrates are then ubiquitinated and broken down by the proteasome.

The use of imide-like compounds in PROTACs and molecular glue drugs represents a significant advancement in drug discovery and chemical biology. It allows for the targeting of previously "undruggable" proteins, expanding the therapeutic landscape. Furthermore, such strategy offers a controlled method to degrade specific proteins, providing a high degree of specificity and reducing off-target effects common in traditional small molecule inhibitors. The adaptability of imide-like compounds in forming the core of PROTACs and molecular glues underscores their potential in creating a new class of therapeutics that could revolutionize the treatment of complex diseases such as cancer, neurodegeneration, and autoimmune disorders.

Our small molecule library of imide-like compounds offers a multipurpose toolkit for drug discovery research, enabling the rapid screening and identification of candidates with potential therapeutic activity. This library accelerates the process of finding novel modulators of protein-protein interactions, especially in the context of targeted protein degradation, such as PROTACs and molecular glue drugs. Furthermore, the diversity of chemical structures within this library provides a broad range of starting points for the optimization of pharmacokinetic and pharmacodynamic properties, significantly enhancing the efficiency and success rate of developing new drugs.

Protacs and Molecular Glues have emerged as pivotal strategies in contemporary drug discovery, offering promising avenues to target proteins previously deemed "undruggable" [1]. These methodologies complement conventional drug discovery approaches, particularly in tackling challenging molecular targets.

While early successes were often attributed to fortuitous scientific discoveries, present-day endeavors heavily lean on rational design principles [2].

To facilitate these research initiatives, we present a curated selection of compounds from the ChemDiv stock. These compounds feature "warhead" fragments designed to target E3 ligases identified in PROTAC DB 2.0 [3].

An essential aspect of our efforts involves ensuring the streamlined development of hit and lead compounds, with a specific focus on regulating ADMET-related properties from the outset [4]. Additionally, the IMiD library offers various potential applications: 

a) Direct screening for potential Molecular Glues.

b) Utilization as a source of available warheads for the construction of new PROTACs.

c) Providing a repository of medicinal chemistry concepts in both categories.

References

1. Liang, X. et al. // Medicinal Research Reviews, 2024, 44(2), 632-685. 10.1002/med.21992

2. Békés, M. et al. // Nature Reviews Drug Discovery, 2022, 21(3), 181-200. 10.1038/s41573-021-00371-6

3. Weng, G. et al. // Nucleic acids research, 2023, 51(D1), D1367-D1372. 10.1093/nar/gkac946

4. Apprato, G. et al. // ACS Medicinal Chemistry Letters, 2023, 14(7), 879-883. 10.1021/acsmedchemlett.3c00231