Identification of inhibitor for protein arginine methyltransferase 4 (PRMT4) by using computer assisted drug design (CADD)

Undergraduate #2
Discipline: Biological Sciences
Subcategory: Cancer Research

Zoya Anderson - Stillman College
Co-Author(s): Anghesom Ghebremedhin, Ahmad Salam, Clayton Yates, and Balasubramanyam Karanam, Tuskegee University, Tuskegee, AL

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Worldwide, breast cancer is the most common cancer observed in women accounting for 25% of all cancers, with 1.7 million new cases diagnosed since 2012. It is one of the leading causes of death among women in the United States. Although Caucasian women are more likely to be diagnosed with the disease, the breast cancer mortality for African American women is about 40% higher than it is for Caucasian women. This is due to the fact that African American women are more likely to be diagnosed with aggressive subtypes of breast cancer. Therefore, novel therapeutic treatment targets need to be discovered and tested. The protein arginine methyltransferases (PRMTs) are a family of enzymes that catalyze arginine methylation and are implicated in a myriad of cellular pathways including transcription, DNA repair, RNA metabolism, signal transduction, protein–protein interactions and subcellular localization. In breast cancer, the expression levels and enzymatic activity of a number of PRMTs are dysregulated; significantly altering the regulation of many cellular pathways that are implicated in breast cancer development and progression. In this study, a novel peptide, termed compound 11, was identified using computer assisted drug discovery against PRMT4. It was hypothesized that this peptide drug would behave as a treatment against aggressive breast cancer by reducing cell viability. The drug was evaluated against an aggressive breast cancer cell line MDA-MB-231 by using in vitro apoptotic assays namely MTT assay, clonogenic assay, and Annexin V staining. Although preliminary, the results indicate that the peptide drug has the potential to serve as a therapeutic treatment for aggressive breast cancer. However, to determine the drug’s full potential, its toxicity will be tested on normal epithelial cells. Also, Western Blot and qPCR analyses will be run to validate the PRMT4 inhibition. Finally, the efficacy of compound 11 will be tested on animal models.

Funder Acknowledgement(s): This research was funded by the National Science Foundation Grant# DMR-1358998.

Faculty Advisor: Balasubramanyam Karanam, bkaranam@mytu.tuskegee.edu

Role: For this research, I performed the assays that evaluated the discovered compound against the aggressive breast cancer cells. I also analyzed and organized the data into graphs and figures.