Katie is originally from Augusta, Georgia and obtained her B.S. in chemistry from Mercer University in nearby Macon, Georgia. She then moved to Bloomington, Indiana to pursue her doctorate working in the lab of Kevin Brown at Indiana University. Her research focused on developing methods to enable stereospecific alkene difunctionalization. After obtaining her Ph.D., Katie joined the discovery chemistry group at Merck in Boston, MA where she is currently a senior scientist working on neuroscience drug discovery.
Abstract:
Leucine-Rich Repeat Kinase 2 (LRRK2) inhibition represents a genetically supported mechanism for disease modification of Parkinson’s disease (PD). Extensive studies have linked gain of function mutations in the catalytic domains to increased risk for familial PD, and increased LRRK2 kinase activity is linked to idiopathic PD. Thus, there is significant research ongoing to develop brain penetrant small molecule LRRK2 inhibitors.
Our medicinal chemistry strategy to optimize kinase inhibitors for a CNS indication was overhauled on an advanced chemical series due to an increased translational risk of low brain penetration that was not sufficiently predicted by P-gp transporter profiling. Further investigations implicated a BCRP transporter liability present on the series. Guided by property-based drug design and expanded transporter profiling, the N-heteroaryl indazole series was reinvented with significantly improved in vitro transporter profiles that reliably translated to in vivo brain penetration. Further optimization of the series was enabled by structure-based drug design which resulted in the identification of a highly selective, potent, and brain penetrant LRRK2 inhibitor.
Symposium Organizing Committee: Brian Aquila, Mark Ashwell, Scott Edmondson, Dan Elbaum, Jeremy Green, Paul Greenspan, Adrian Hobson, Blaise Lippa, Lisa Marcaurelle, Min Lu, Kap-Sun Yeung, Andrew Scholte, Mala Gopalsamy, Raj (SB) Rajur (Chair)
