Modeling the Targeting of RNA‐Binding Proteins Using Small Molecular Inhibitors: A Novel Approach For Cancer Treatment

Abstract

RNA Binding Proteins (RBPs) are proteins that bind to single or double‐stranded RNA in cells leading to the formation of ribonucleoprotein complexes. RBPs contain different structural motifs including RNA recognition motif (RRM), dsRNA‐binding domain, zinc‐finger etc. RBPs play an important role in splicing, polyadenylation, mRNA stabilization, mRNA localization, and translation. The Olathe North MSOE Center for BioMolecular Modeling SMART Team used 3‐D modeling and printing technology to examine structure‐function relationships of a RBP. To discover the interactions between proteins or modifications in RNA, cross‐linking and immunoprecipitation (CLIP) assays are used. Several techniques have been based off CLIP including photoactivatable‐ribonucleoside‐enhanced crosslinking and immunoprecipitation (PARCLIP), high‐throughput sequencing of RNA isolated by crosslinking (HTS‐CLIP), individual nucleotide resolution Cross‐Linking and Immunoprecipitation (ICLIP), etc. are also developed. RNA binding proteins have a wide variety of functions, and they are involved in many steps of cancer development and progression. Abnormal expression of RBPs is linked with the survival rate of cancer patients. RBPs role in cancer varies from protein to protein, as some proteins are overexpressed, underexpressed, or deregulated in certain cancers. When RBPs are deregulated (caused by factors such as genomic alterations, epigenetic mechanism, noncoding RNA‐mediated regulation, and PTMs), they target RNAs, which affects the characteristics of cancer cells. Hence, they serve as an attractive target for cancer drug discovery. Among RBPs, RNA‐binding protein RBM3 can bind to the AU rich sequences in the mRNA. This was shown to induce colon carcinogenesis. RBM3 has also been shown to stabilize rapidly degrading mRNAs like cyclooxygenase 2 (COX‐2), interleukin‐8 (IL‐8), and vascular endothelial growth factor (VEGF). RBM3 also increases translation on a global level by interacting with the 60S ribosome. Previous studies have shown that RBM3 acts as protooncogene in colon cancer, it induces stem‐like characteristics in colon cancer cells by increasing side population, spheroid formation and increased the expression of stem cell markers such as DCLK1 and LGR5. Recently, Dr. Anant's group found that RBM3 plays a significant role in chromatin remodeling at the DCLK1 locus thereby enhancing expression of the short form of the protein thereby increasing stem‐like phenotype in colon cancer cell lines. Targeting RBM3 using small molecular inhibitors is hypothesized to be a probable treatment for colon cancer. To predict small molecules targeting RMB3, we used homology modeling technique study to generate a 3D‐protein structure of RBMs. IDOCK and I‐TASSER servers are used to perform virtual screening of small molecules. Structural‐based drug design method is used to design small molecules that can target RBM3. These compounds will serve as lead molecules for future drug design and discovery.Support or Funding InformationSponsors: Chris Elniff and LB Fogt Mentor: Dr. Prasad Dandawate and Dr. Shrikant Anant, Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS66160.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.