Grafton Ervine
Pronouns:
Research Mentor(s): George WANG
Research Mentor School/College/Department: Pathology-MCTP / Medicine
Program: UROPF
Session: Session 7 (4:40pm – 5:30pm)
Authors: Grafton Ervine, Rudana Hamadeh, Xiaoju Wang
Abstract
In breast cancer, cyclin-dependent kinases 12 and 13 (CDK12/13) are families of protein kinases that regulate transcription and mRNA processing. CDK12 and CDK13 are important regulators of RNA transcription and cell cycle progression and cell proliferation. In our recent study (JMC), we identified a series of dual CDK12/13 degraders in therapies for triple-negative breast cancer (TNBC) by employing proteolysis-targeting chimera (PROTAC) technology. The optimal compound, 7f, exhibited potent cell proliferation inhibition and in vivo degradation in TNBC models. Based on 7f, we developed a new version of the CDK12/13 degrader. In vitro studies demonstrated that the new CDK12/13 degraders have a superior effect on cell growth inhibition and DNA damage in multiple prostate cancer cells, effectively suppressing the proliferation of the tumor cells. In this study, we will generate an in vivo xenograft model to test the efficacy of the newly discovered dual CDK12/13 degraders. Tumor cells will be injected into live subjects and allowed to grow over time, until a necroscopy procedure is performed. All the other organs, including the liver, spleen, kidney, etc., will also be collected for further toxicity analysis. We anticipate that the new CDK12/13 degrader inhibits tumor growth and induces DNA damage.
