A Multidisciplinary Approach to Cancer Treatment: Computational-Guided Discovery of Novel PRMT5 Inhibitors

Research Presentation

My presentation on the Discovery and Enhancement of Novel PRMT5 Inhibitors to Optimize Brain Cancer Treatment

Research this summer was truly a life changing experience. The long hours at night to finish an experiment were very frustrating at first. However, by continually doing research, I began to see the importance of patience. My biggest growth in this experience was developing patience; I didn’t grow patience out of habit, but because I began focusing on my goal, which is to contribute to a cure against brain cancer.

While I worked on various projects for Dr. Chenglong Li and Dr. Robert Baiocchi, my focus was to combine biological assays with computer-aided molecule optimization to efficiently create novel molecules to inhibit the functionality of Protein Arginine Methyltransferase 5 (PRMT5). PRMT5 is a novel enzyme that is consistently overexpressed in Glioblastoma, a malignant brain tumor that leaves patients with only ~18 months left to live. I identified novel and effective PRMT5 inhibitor, Compound Intermediate 18 (ICD18) through cell proliferation screening. ICD18 has an affinity level of -5.1 kcal/mol towards PRMT5’s active site and is capable of eradicating 50,000 Glioblastoma cells at 10 μM –25 μM. After discovery, I optimized ICD18 through molecular optimization, doubling its affinity and attaining a stronger affinity level towards PRMT5 than PRMT5’s cofactor, S-adenosyl methionine (SAM). SAM contained a -8.4 kcal/mol affinity towards PRMT5’s active site; my optimized compound, ICD18p, contained a stronger affinity of -10.0 kcal/mol. After optimization, I developed a 4 more structures based off my previous optimization to simulate a “cocktail therapy” to counter biomolecule resistance. To conduct this research, I initiated collaborative work in The College of Pharmacy and The Comprehensive Cancer Center. With 100+ hrs. of benchwork and 50+ hrs. of molecular designing and optimizations, this experience has given me a deep appreciation for the multidisciplinary and collaborative approaches in healthcare.

This experience has given me such a great view on medicine and has refined my professional goals. I want to change the world by developing cures to diseases in my immediate community and abroad. Thank you STEP for allowing me to take on this wonderful experience. It has truly changed my life.

 

Thank you,

Joshua Ong