Pharmacology, Toxicology and Environmental Health Commons^™

Utilizing Proteolysis-Targeting Chimeras To Target The Transcriptional Cyclin-Dependent Kinases 9 And 12, Hannah King

Theses & Dissertations

Cyclin-dependent kinases (CDKs) are a family of serine-threonine kinases involved in various cellular functions, such as regulating the cell cycle and gene transcription. CDK9, a transcriptional CDK, regulates highly expressed enhancer-associated oncogenic transcription factors, including the oncogene Myc. CDK9 is responsible for the transcription and stabilization of Myc; consequently, it was a validated target for pancreatic cancer treatment.

As such, we developed a panel of aminopyrazole based proteolysis targeting chimera where we identified PROTAC 2 as a selective degrader of CDK9 (DC₅₀ = 158 ± 6 nM). PROTAC 2 was capable of cereblon mediated proteasomal degradation of CDK9 while …

Delivery Of Small Molecule And Rna Using Synthetic Polymeric Micelles And Multifunctional Exosomes For The Treatment Of Type 1 Diabetes, Yang Peng

Theses & Dissertations

Type 1 diabetes is one of the most challenging chronic autoimmune diseases. The destruction and dysfunction of insulin-secreting β cells are the results of inflammatory infiltration and the synergistic effect of multiple immune cells. The aim of this dissertation is to develop novel and reliable therapeutic approaches to advance the treatment of T1D: including chemical modification of a broad-spectrum immunosuppressant, co-application of small molecule based immune intervention and siRNA based β cell preservative therapy, and administration of a PI3K-δ/γ dual inhibitor to specifically target immune cells, utilizing synthetic polymeric micelles or natural produced multi-functional exosomes derived from human bone marrow …