Plenary Address, Novel drug targets and novel drugs using proteomics technology

Sudhir Sahasrabudhe, Ph.D.
CEO, Rines Therapeutics
Research Professor of Medicinal Chemistry, University of Utah, USA

NOVEL DRUG TARGETS AND NOVEL DRUGS USING PROTEOMICS TECHNOLOGY

Translational medicine is the conversion of scientific discovery into improvement of human health. The key to any translational medicine effort is to make sure that the novel inter-disciplinary research advances in the laboratory find their way to the clinic to better serve patients with unmet medical need. This talk will feature 2 such efforts:

Example 1:
We established a chemi-proteomics platform to capture and identify proteins that bind to small molecule hits from a cell-based genetic screen. This screen was geared to identify molecules that are selectively lethal to cells with aberrantly active RAS-signaling pathway (Nature: 447, 865, 2007; Nature Methods:7, 801, 2010). This effort helped identification of a novel cancer target and paved the way for creation of a novel small molecule currently in clinical Proof-of-concept (Phase 2a) studies in cancer patients

Example 2:
Huntington’s disease (HD) is a fatal neurodegenerative condition caused by expansion of the polyglutamine tract in the huntingtin (Htt) protein. Neuronal toxicity in HD is thought to be a consequence of protein interactions involving mutant Htt. We therefore hypothesized that genetic modifiers of HD neurodegeneration should be enriched among Htt protein interactors (PLOS Genetics: 3(5), 2007). To test this idea, we identified a comprehensive set of Htt interactors using two complementary approaches: high-throughput yeast two-hybrid screening and affinity pull down followed by mass spectrometry. This effort led to the identification of 234 high-confidence Htt-associated proteins, 104 of which were found with the yeast method and 130 with the pull downs. We then tested an arbitrary set of 60 genes encoding interacting proteins for their ability to behave as genetic modifiers of neurodegeneration in a Drosophila model of HD. This presentation will outline the identification and validation of novel drug targets for HD.