As known, RNA-binding proteins (RBPs) play critical roles in various cellular processes, including gene expression and RNA metabolism. Their dysregulation linked to tumorigenesis has made them promising targets in cancer drug discovery. Hence, small-molecule targeting of RNA-associated proteins can open up good opportunities for highly selective treatment of disorders affecting cellular processes [1].
With this in mind, Life Chemicals has developed its RNA-associated Protein Screening Library of over 6,500 drug-like small-molecule compounds as a promising starting point for drug discovery research in the areas associated with post-transcriptional gene regulation and anticancer drug development.
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
Although RNA-targeting compounds keep gaining attention as potential therapeutic agents, proteins remain the primary targets of clinically-approved small-molecule drugs. The development of new drugs targeting RNA-associated proteins has been enabled by advances in structural biology, which provided insights into the mechanisms of RNA-protein interactions.
RNA-associated proteins have been regarded as "undruggable" for a long time due to often noncatalytic and complex interactions with RNA, limiting the design of specific inhibitors. Nonetheless, several small-molecule inhibitors have recently been discovered for various RNA-associated protein targets. In particular, this strategy has been employed to target oncogenic miRNA [2] and HIV [3], with these inhibitors being predicted to be effective as antifungal agents [4]. Therefore, by modulating the activity of RNA-associated proteins, it can be possible to treat several diseases from cancer to viral infections.
Compound Selection
Firstly, a reference set of molecules that were reported as RNA-associated protein binding-capable was collected from the literature sources, using PDB and ChEMBL databases. Then it was constricted by binding activity via discarding compounds with a low dissociation constant (Kd > 10 μM; Inhibition, IC50, etc. ≤ 10μM).
Next, a 2D similarity search was performed against the Life Chemicals HTS Compound Collection, keeping the high value of diversity (Tanimoto and Tversky index ≥ 0.80 and ≥ 0.85, respectively). As a result, over 6,500 drug-like compounds with predicted RNA-associated protein binding activity have been selected for the resulting Screening Set.
Figure 4. Screening compound distribution by the type of the targets in the RNA-associated protein Screening Library.
Representative compounds from the Life Chemicals RNA-associated Protein Screening Library
References
- Childs-Disney, Jessica L et al. “Targeting RNA structures with small molecules.” Nature reviews. Drug discovery vol. 21,10 (2022): 736-762. doi:10.1038/s41573-022-00521-4
- Vo, Duc Duy et al. “Oncogenic MicroRNAs Biogenesis as a Drug Target: Structure-Activity Relationship Studies on New Aminoglycoside Conjugates.” Chemistry (Weinheim an der Bergstrasse, Germany) vol. 22,15 (2016): 5350-62. doi:10.1002/chem.20150509
- Patwardhan, Neeraj N et al. “Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR.” MedChemComm vol. 8,5 (2017): 1022-1036. doi:10.1039/C6MD00729E
- Zhang Y, Bell A, Perlman PS, Leibowitz MJ. Pentamidine inhibits mitochondrial intron splicing and translation in Saccharomyces cerevisiae. RNA. 2000;6(7):937-951. doi:10.1017/s1355838200991726