Senior Director and Global Head of Molecular and Cellular Pharmacology
April 25th, 2016 – Spring Seminar
Time and location: Noon at Public Policy 105
“Impact of Enzymology on Drug Discovery”
Enzymology continues to play a pivotal role in drug discovery. I will discuss the drug discovery projects below where development of a detailed understanding of the mechanism of enzyme inhibition was critical in driving the structure-activity relationship data, determining target engagement, understanding pharmacokinetic-pharmacodynamic relationships, and selecting clinical candidates. I will also present an example showing how developing the “right” assay was essential to intelligently determine the fate of the project.
1. Fatty acid amide hydrolase (FAAH) inhibitor
2. Sirt1 activator
3. Diacylglycerol acyltransferase 2 inhibitor
Host: Dr. Songon An
Ahn, Kay, et al. “Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain.” Journal of Pharmacology and Experimental Therapeutics 338.1 (2011): 114-124.
Ward, Jessica, et al. “Mechanistic characterization of a 2-thioxanthine myeloperoxidase inhibitor and selectivity assessment utilizing click chemistry–activity-based protein profiling.” Biochemistry 52.51 (2013): 9187-9201.
Ruggeri, Roger B., et al. “Discovery of 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3, 4-dihydropyrimidin-1 (2 H)-yl) acetamide (PF-06282999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases.” Journal of medicinal chemistry 58.21 (2015): 8513-8528.