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Prof Kay Ahn

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”

Abstract

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

Related Articles:

Ahn, Kay, et al. “Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain.” Chemistry & biology 16.4 (2009): 411-420.

Mileni, Mauro, et al. “Structure-guided inhibitor design for human FAAH by interspecies active site conversion.” Proceedings of the National Academy of Sciences 105.35 (2008): 12820-12824.

Johnson, Douglas S., et al. “Discovery of PF-04457845: a highly potent, orally bioavailable, and selective urea FAAH inhibitor.” ACS medicinal chemistry letters 2.2 (2010): 91-96.

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.

Pacholec, Michelle, et al. “SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.” Journal of Biological Chemistry 285.11 (2010): 8340-8351.

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.

Futatsugi, Kentaro, et al. “Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2).” Journal of medicinal chemistry 58.18 (2015): 7173-7185.

Ahn, Kyunghye, et al. “Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity.” Biochemistry 46.45 (2007): 13019-13030.