Development of PROTAC-based degrader of ERG transcription factor in prostate cancer

Rudana Hamadeh

Pronouns: she/her

Research Mentor(s): George WANG
Research Mentor School/College/Department: Pathology-MCTP / Medicine
Program: UROPF
Session: Session 7 (4:40pm – 5:30pm)
Authors: Rudana Hamadeh, Grafton Ervine, George Wang

Abstract

Derangement and hyperactivity of cyclin in the cell cycle can lead to rapid diving, or proliferation, of cells in the body, which assists in the formation of cancer. Cyclin-dependent kinases 12 and 13 (CDK 12/13) play a significant role in this process, as they have the function of regulating gene transcription. The ability to inhibit both CDK 12/13 simultaneously has the potential to become a treatment of triple-negative breast cancer cells. Recently our group has identified a dual CDK12/13 degrader using proteolysis-targeting chimera (PROTAC) technology (J. Med. Chem. 2022). The compound “7f” was effective in degrading CDK 12 at 2.2 nanomolar and CDK 13 at 2.1 nanomolar, therefore inducing DNA damage as well as preventing the proliferation of triple-negative breast cancer cells. In terms of in vivo research, after removing the tumor tissues and injecting them with “7b”, a similar compound to “7f”, we found that both CDK 12 and 13 were both degraded 6 hours after treatment, bearing evidence for a strong and fast degradation efficiency. In this study, we propose to apply the degrader on a prostate cancer model. In vitro, we will test the cell viability of multiple prostate cancer cell lines using Cell TiterGlo. In vivo, we will generate an in vivo xenograft model to assess its efficacy. Specifically, we can investigate the toxicity of different organs and the efficacy of the degraders.

Health Science