Title: Polycyclic Cage Molecules in CNS Drug Design

Speaker: Prof. Michael Kassiou

Abstract: The social, clinical and economic need for improved therapies for central nervous system (CNS) disorders is critical. They represent approximately 10% of the global burden of disease and finding drug treatments for CNS disorders such as dementia is incredibly challenging. They are extremely complex health problems typically difficult to diagnose and difficult to treat given that drugs struggle to get into the brain’s largely separate blood supply. As such CNS drugs require significantly longer development times than non-CNS drugs and are significantly more likely to fail in Phase III development. As the pharmaceutical industry continues to reprioritise and focus on low-risk, relatively short-term gains, there are tremendous opportunities for academic drug discovery in the challenge of discovering drugs to address real unmet needs.

The Kassiou group has been addressing this challenge through the use of polycyclic cage molecules, such as adamantane (tricyclo[3.3.1.1^3,7]decane),  trishomocubane (hexacyclo[5.4.0.0^2,6.0^3,10.0^5,9.0^8,11]undecane, and cubane (pentacyclo[4.2.0.0^2,5.0^3,8.0^4,7]octane, in CNS drug design. These polycyclic cage molecules have attracted the attention of the synthetic chemistry community for decades, largely due to the synthetic challenge imposed by their unique architectures. More recently, they have been increasingly utlised by medicinal chemists in the design of novel drugs with diverse therapeutic activity. Polycyclic cage molecules provide unique opportunities in the development of CNS bioactive molecules due to their rigid molecular structures and the ability to position substituents or pharmacophoric groups with precise three-dimensional orientation. Moreover, they can used in the alteration of lipophilicity when incorporated into a potential drug molecule as a pendant unit or as a core allowing easier access across cellular membranes and the blood-brain barrier. This presentation will describe some of our efforts in this area.

Speaker Bio: Michael Kassiou is Professor of Medicinal Chemistry, NHMRC Principal Research Fellow and Academic Director of the Drug Discovery Initiative at the University of Sydney. He leads extensive programs which combine chemistry and biology platforms for development of bioactive molecules. He has over 290 publications receiving over 10,000 citations. His research program has seen three new compounds progressed to first-in-human studies for the imaging of neuroinflammation in a variety of CNS disorders. In the last 5-years his innovations in small molecule therapeutics has resulted in the formation of 3-spin off companies which he hopes will provide novel treatments for diseases of the brain. He has been elected Fellow of several international societies, including the Asian Federation of Medicinal Chemistry, the Royal Society of Chemistry, and the Society of Radiopharmaceutical Sciences. He has been awarded several prizes including the the Adrien Albert Award in Medicinal Chemistry and the RACI Applied Research Medal in 2020. He is Chief Editor for Frontiers in Medicinal and Pharmaceutical Chemistry and Associate Editor for ACS Chemical Neuroscience.