Design and Investigation of Small Molecule Drugs for Potential Treatment of CNS Disorders, Flaviviral Infections, and Cancers

Chapter 1 discusses the development of antagonists against the dopamine 4 receptor (D4R) that is expressed in the motor, associative, and limbic subdivisions of the basal ganglia network and is involved in Parkinson’s disease (PD). Levodopa is the firstline drug for the management of PD symptoms but its long-term use often leads to development of levodopa-induced dyskinesia (LID). D4R antagonists have been shown to decrease the abnormal involuntary movement scores in mouse models of LID. Chapter 1 outlines the development and optimization of selective D4R antagonists for potential treatment of LID. During the investigation of our D4R antagonists we discovered that they displayed activity against sigma 1 receptor (σ1R) - a multifunctional receptor, involved in a variety of neurological conditions. We report the results of the investigation of D4R antagonists for their role as σ1R modulators. Chapter 2 outlines our efforts to develop inhibitors against some or all of flaviviruses. Flaviviruses are positive-stranded RNA viruses that include the disease agents: Dengue, Zika, West Nile, Yellow fever, and Japanese encephalitis. In collaboration with our partners we developed a hypothesis that inhibiting the key flaviviral enzyme RNA-dependent RNA polymerase would lead to the decrease of more than one type of flavivirus. We developed and optimized a library of flaviviral inhibitors and had them tested for activity and toxicity. We identified potent flaviviral inhibitors and developed a lead scaffold that displayed activity against more than one type of flavivirus, thus providing support for our hypothesis. Chapter 3 discusses the investigation of inhibitors of claudin-1 protein for potential treatment of colorectal cancer (CRC). CRC is the third most commonly diagnosed cancer worldwide and one of the most lethal cancer types. Studies implicate claudin-1 in the development of metastasis and drug-resistance in CRC. We designed a diverse library of claudin-1 inhibitors and performed a structure-activity relationship study resulting in the identification of a potent lead scaffold and targets for future optimization. Chapter 4 describes the development of inhibitors and degraders against the microtubule-associate serine/threonine kinase like (MASTL), a key regulator of mitosis, overexpressed in a number of cancers, including CRC. Proteolysis-targeting chimeras (PROTACs) are heterobifunctional protein degraders that potentially possess significant advantages over the small molecule inhibitors. We designed the first-of-a-kind library of MASTL PROTACs and investigated them for activity against MASTL side-by-side with MASTL inhibitors. We outline the synthetic procedures, results of our investigation, and discuss future directions for the development of these promising therapeutic tools.