Most childhood cancer therapeutics stem from adult cancer therapeutics. These non-tailored treatments aren't effective on childhood cancer and have adverse side effects that dramatically reduce the quality of life (Houghton and Kurmasheva, 2019). More effort towards treating childhood cancer using alternative methods is crucial.
Ribonucleic acid (RNA)-binding proteins (RBPs) are essential modulators of RNA homeostasis (Pereira et al. 2017). Deregulation of RBP-RNA interactions leads to many diseases, including cancer (Wang et al. 2019). Advancements in mass spectrometry and RNA sequencing have allowed for transcriptome and proteome-wide analysis of these RNA-protein interactions (Nechay and Kleiner, 2020). Not only do these advances allow us to further our understanding of the mechanisms behind RBP-RNA interactions, but it also provides us promising avenues to exploit a tailored drug-based cancer therapeutic approach.
Small molecule chemical probes (SMCPs) are useful to target individual RBPs (Julio and Backus, 2021). They can decipher a function of specific structural features of RBPs and can be used as a cost-effective drug therapeutic. Recent RBP structural knowledge advancement of cysteine residues has shifted the once thought to be 'undruggable' protein class to a promising target for SMCPs (Juilo and Backus, 2021). The increased specificity with and potency of targeting cysteines within RBPs using SMCPs allows for a highly selective, cost-effective therapeutic with potential for clinical use for various childhood cancers Kwoatkowski et al. 2014).
Therefore, we aim to:
1. to identify tractable RBP targets in childhood cancers using chemoproteomic data mining
2. validate the biological relevance of discovered RBPs in different childhood cancer cell lines
3. To identify chemical probes targeting biologically relevant RBPs
4. To design novel chemical probes for RBPs.
Current findings suggest out of 684 cysteine-targetable RBPs, 6 biologically relevant neuroblastoma protein targets are available for further analysis with currently accessible highly selective chemical probes. The best 4 targets were validated in vitro to be biologically relevant, and their corresponding chemical probes were confirmed to selectively target these RBPs. This provides evidence towards novel neuroblastoma protein targets, but more importantly, these results provide evidence towards a computational pipeline that can be used for drug discovery for varying cancers.