Title: Efforts on Speeding up Translational Research: From Phenotypic Screening Hits to Animal Models

Lecturer: Dr. Zhiyuan Zhang

                Investigator

                Director of Translational Research Center,

                National Institute of Biological Sciences, 

                Beijing, China.

Time: AM 10:00, March 11, 2016 (Friday).  

Venue: Lecture hall E307, School of Life Sciences. 

Invitor: Prof. Xianming Deng

Lecture Abstract: Phenotypic screening has played important role in drug discovery and new target identification. Today, it is rather easy to obtain screening hits through high throughput screening of compound library, however finding its target is a formidable task. Our research focus on translational research, unlike doing it in traditional way, our research involve in a project at very early stage of basic research, which includes developing SAR, probe design for target identification and evaluations, medicinal chemistry and animal model studies. We have successfully applied this strategy in the study of cell necrosis and apoptosis signaling pathway with collaboration with other groups. We first optimized the low affinity hits to high affinity NCEs, followed by designing affinity probes for target identification, further Med-Chem efforts enable us to deliver high quality NCEs that can give more reliable results during the animal model study. For example, starting from a screening hit we have successful identified its targeting protein RIP1, and the final RIP1 inhibitors are highly potent and selective, have good metabolic stability and low toxicity. Efficacy study shown 100% protection on mouse death model induced by TNF-, comparing to 10% survival rate in untreated group. To facilitate the target identification process, we have developed a more efficient and highly accurate technology BTC-ABPP that can greatly increase target protein labeling and can remove all fake candidates, therefor greatly shorten the time on target identification. We also developed a life imaging system that allows us to effectively labeled the target protein-bound probe at cell level or even in living beings (worm), to figure out the location of the target protein.

Personal Profile: Dr. Zhiyuan Zhang is an investigator and director of Translational Research Center, at National Institute of Biological Sciences, Beijing (NIBS). He is a medicinal chemist and the inventor of two marketed anti diabetes drugs, Alogliptin and Trelagliptin, which Dr. Zhiyuan Zhang invented at Takeda pharmaceuticals San Diego before he joined NIBS. At Takeda, he was a principal scientist, awarded “Takeda Global award” and “Structure Based Drug Design Award”, he also invented several other clinical candidates that entered clinical trails. He was a founding scientist of a biotech company, called Optimer Pharmaceuticals (in US, OPTR) that was founded based on the OPopS technology invented by him when he worked as a post-doctoral fellow at The Research Institute of Scripps. He obtained his Ph.D. degree in organic chemistry from Lund University Sweden, and his BS degree in organic chemistry from Nankai University China. Now Dr. Zhang is an investigator and director of translational research center at NIBS, in charge of translational research. His research interests include drug discovery in the fields of diabetes, cancer, HBV infection and inflammation. Dr. Zhiyuan Zhang also is interested in developing new technology for target identification using activity based probe derived from phenotypic screening hits, and biological image system mediated through activity based probe for studying the location and behave of target protein.