Julia Garfin
Research Mentor(s): Yihan Liu
Mentor Department: Department of Pathology, Parolia lab
Authors: Julia Garfin, Yihan Liu
Session: Session 6 (3:00pm – 3:50pm)
Presentation Type: Poster 109
Abstract
Nuclear receptor-binding SET domain-containing 2 (NSD2) is a cofactor of the Androgen Receptor (AR), which is known to contribute to the oncogenic process of prostate cancer as well as other cancers (1). In a previous study, it was discovered that the compound LLC0424 is a highly selective degrader of the NSD2 protein (2). This was determined via the proteolysis targeting chimera (PROTAC) approach. While this compound proved to be effective in suppressing cell growth and activity, longer periods of time revealed that NSD1, a NSD2 paralog, has a compensatory function for NSD2. Therefore, it is crucial to develop a compound that targets both NSD1 and NSD2 to be cytotoxic on AR+ prostate cancer. In this experiment, several compounds were studied. The cells treated by compounds are harvested for protein and loaded into a gel in order to run a Western Blot experiment. When the gel finishes running, the membranes undergo antibody probing with a primary, protein-specific, antibody, followed by a secondary, anti-species (mouse or rabbit), antibody. Finally, using a luminescence signal, the membranes were read out to determine the amount of NSD1, NSD2, and H3K36me2 (enzymatic product of NSD1 and NSD2) present in cell lines. Through this study, we can determine if certain compounds are effective degraders of the NSD1 and NSD2 cofactors of the androgen receptor. References: 1. Abhijit Parolia; Sanjana Eyunni; Verma, B. K.; Young, E.; Liu, L.; George, J.; Aras, S.; Das, C. K.; Mannan, R.; Rasool, R. ur; Luo, J.; Carson, S. E.; Mitchell-Velasquez, E.; Liu, Y.; Xiao, L.; Gajjala, P. R.; Jaber, M.; Wang, X.; He, T.; Qiao, Y. NSD2 Is a Requisite Subunit of the AR/FOXA1 Neo-Enhanceosome in Promoting Prostate Tumorigenesis. bioRxiv (Cold Spring Harbor Laboratory) 2024. https://doi.org/10.1101/2024.02.22.581560. 2. Liu, L.; Abhijit Parolia; Liu, Y.; Hou, C.; He, T.; Qiao, Y.; Sanjana Eyunni; Luo, J.; Li, C.; Wang, Y.; Zhou, F.; Huang, W.; Ren, X.; Wang, Z.; Chinnaiyan, A. M.; Ding, K. Discovery of LLC0424 as a Potent and Selective in Vivo NSD2 PROTAC Degrader. Journal of Medicinal Chemistry 2024, 67 (9), 6938–6951. https://doi.org/10.1021/acs.jmedchem.3c01765.
