Drug Target Strategies

Serine Hydrolase Drug Discovery by Activity-based Protein Profiling

Wednesday, February 7
2:00 PM - 2:30 PM
Location: 6D

Serine hydrolases are one of the largest known enzyme classes comprised of over 250 members in humans. These enzymes have diverse physiological roles in metabolism, inflammation, neurotransmission, and blood clotting through the production or degradation of a wide range of bioactive molecules. While some members of this class are well-characterized and even the targets of approved drugs, many members of the serine hydrolase family remain uncharacterized with respect to their biochemical and physiological functions in large part due to the lack of tools to investigate these enzymes in living systems.

Activity-based protein profiling (ABPP) has emerged as a powerful chemoproteomic approach for serine hydrolase inhibitor development. Here, we show how Abide Therapeutics has used ABPP to enable the discovery, optimization and characterization of a diverse collection of inhibitors for members of this class. Furthermore, we demonstrate how this technique provides a unified activity, selectivity and target engagement assay applicable to each stage of serine hydrolase drug discovery, from primary screens to clinical trials in humans.

Micah Niphakis

Senior Scientist
Abide Therapeutics

Micah Niphakis received a B.S. in Chemistry from Houghton College and began his graduate studies in 2005 in the Department of Medicinal Chemistry at the University of Kansas with Professor Gunda I. Georg. In 2007, he relocated to the University of Minnesota with Professor Georg where he completed his Ph.D. on the synthesis and biological activity of phenanthropiperidine alkaloids. He then joined the lab of Professor Benjamin F. Cravatt III at the Scripps Research Institute as a Ruth L. Kirschstein NIH postdoctoral fellow. His postdoctoral research focused on the development of serine hydrolase inhibitors and chemical tools to comprehensively map lipid and small molecule interactions in cells. In 2014, he joined Abide Therapeutics as a medicinal chemist and chemical biologist where he is developing chemical tools and techniques to enable serine hydrolase drug discovery.

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