UC San Diego

Glioblastoma (GBM) represents the most prevalent malignant tumor affecting the central nervous system. The current treatment regime consisting of surgery, chemotherapy, and radiation has remained the same for over two decades even though patients rarely live three years past treatment. Post-translational regulation of the repressor element-1 silencing transcription factor (REST) has been shown to be a successful method in reducing GBM derived tumors. Inhibition of REST’s regulatory protein small C-terminal domain phosphatase 1 (SCP1) is an effective strategy to modulate REST levels and therefore GBM. Guided by a structure-based drug design approach over 220 final compounds were synthesized and tested generating a broad understanding of their structure-activity relationship. To better understand the kinetics of the dually activated benzo[b]thiophene 1,1-dioxide warhead, an NMR based kinetic study was performed to generate half-life (t1/2) data and find the target zone of reactivity.The GNAS gene, responsible for encoding the Gαs subunit of heterotrimeric G proteins, exhibits the second highest mutation frequency in mucinous appendiceal adenocarcinoma. Despite being a druggable target, there are currently no commercially available inhibitors specifically targeting Gαs. Additionally, GNASR201 stands out as a target because it is the most cancer-causing mutation of all heterotrimeric G-proteins. As guanosine-5’-triphosphate (GTP) is the Gαs’s endogenous substrate the strategy was to synthesize GTP derivates that covalently bind the GNASR201C mutation allowing selectivity of the cancerous cells. Guanosine-epoxide (2.4) and a diastereomeric pair of its phosphoamidate prodrugs were synthesized and tested showing a proof of concept. Synthetic routes affording cyclic and acyclic covalent guanosine analogues were bottle necked by a phosphorylation step. Although optimization efforts resulted in parameters generating the desired product, reaction yields were insufficient to allow the generation of a diverse library.