T-cell immunoglobulin and mucin domain 3 (TIM-3) is a negative immune checkpoint expressed in many types of immune cells, which participates in the regulation of adaptive and congenital immunity [1]. TIM-3 is an attractive target for treating cancer [1], chronic liver disease [2], chronic viral infections [3], multiple sclerosis [3], etc.
With this in mind, our cheminformatics team has designed a new targeted Screening Set containing over 1,500 drug-like screening compounds with predicted TIM-3 inhibitor activity.
The compound selection can be customized based on your requirements. Cherry-picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Background information
The inhibition of immune checkpoint receptors has significantly improved the treatment of major cancers, including melanoma, Hodgkin's lymphoma, lung and renal cancers. Nevertheless, the overall success rate is still low, and certain cancers, such as microsatellite-stable colorectal cancer, do not respond to these treatments. This has led to the exploration of other checkpoint receptors. T-cell immunoglobulin and mucin domain 3 (TIM-3) is found on various immune cells and leukemic stem cells, making it a promising target for cancer immunotherapy. Blocking both TIM-3 and PD-1 has been shown to decrease tumor growth in preclinical models and enhance antitumor T-cell responses in cancer patients [2].
Recent studies have revealed an alternative binding site on TIM-3, located within the C’’-D loop, in addition to the primary binding site. This novel binding site, identified through X-ray crystallography, involves key interactions with residues W78, W83, R81, and Y82 and features a dual π-π stacking interaction and a hydrogen-bonding network. This alternative binding site presents an opportunity to design small-molecule inhibitors that can complement or enhance the effects of those targeting the primary site. Utilizing this secondary site may offer a synergistic approach to inhibiting TIM-3, potentially overcoming resistance mechanisms and improving therapeutic outcomes [4].
Compound selection
The molecular docking was based on the Life Chemicals HTS Compound Collection. The obtained results demonstrated the feasibility of targeting this alternative site on par with the primary binding site. Our new Screening Library, targeting both primary and alternative binding sites of TIM-3, includes more than 1,500 compounds of potential TIM-3 modifiers and can be used to develop innovative drugs to modulate the immune response against cancer and other diseases effectively.
Key features:
- Method: glide ligand docking (standard precision)
- X-Ray data used: 7M3Z
- Constraints: no
- Filters used: no
- Number of compounds selected: 1,517
Fig. 1. Spatial structure binding site of the complex of TIM-3 (main site) with lead docking molecule F6523-3657 (docking score = -8.16).
Fig. 2. Spatial structure binding site of the complex of TIM-3 (alternative site) with lead docking molecule F0662-1368 (docking score = -10.26).
Representative screening compounds from the Screening Library
Reference:
- Ausejo-Mauleon I, Labiano S, de la Nava D, et al. TIM-3 blockade in diffuse intrinsic pontine glioma models promotes tumor regression and antitumor immune memory. Cancer Cell. 2023;41(11):1911-1926.e8. doi:10.1016/j.ccell.2023.09.001
- Sauer N, Janicka N, Szlasa W, et al. TIM-3 as a promising target for cancer immunotherapy in a wide range of tumors. Cancer Immunol Immunother. 2023;72(11):3405-3425. doi:10.1007/s00262-023-03516-1
- Zhao L, Cheng S, Fan L, Zhang B, Xu S. TIM-3: An update on immunotherapy. Int Immunopharmacol. 2021;99:107933. doi:10.1016/j.intimp.2021.107933