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Expanding at the core
Dr. Bruce Posner has at least 100,000 new reasons why UT Southwestern investigators should consider collaborating with the High-Throughput Screening (HTS) Core in the Department of Biochemistry and the Harold C. Simmons Comprehensive Cancer Center.
The facility recently expanded its chemical screening library by 100,000 compounds, bringing the total number to more than 330,000, says Dr. Posner, Professor of Biochemistry and Director of the HTS Core.
“The High-Throughput Screening Core is devoted to advancing basic research discoveries to translational impact,” he says. “We help principal investigators here at UT Southwestern interrogate biological and pathological systems using either functional genomics and/or chemical screening.”
Supporting the early, preclinical discovery and development of new small molecule therapeutics, the HTS Core helps investigators identify and characterize novel biological targets and pathways for therapeutic intervention in such areas as cancer, neurodegeneration, metabolic diseases, antivirals, and parasitic infections.
“The High-Throughput Screening Core is devoted to advancing basic research discoveries to translational impact.”
The HTS Core was founded in 2002 by former Biochemistry Chair Dr. Steven McKnight, who envisioned a close-knit, multidisciplined research environment in which chemists, biochemists, biophysicists, and cell biologists could advance cutting-edge discoveries in basic research to potential therapeutic approaches using targeted and optimized small molecules, Dr. Posner says.
“To support these efforts, Steve created three core facilities led by faculty members with expertise in high-throughput screening, medicinal chemistry, and preclinical pharmacology, each of which he knew would be absolutely fundamental to advancing basic research toward translational impact for patients,” he says. “The uniqueness of our HTS Core facility is the fact that it’s coupled to these other Cores and to a requisite body of expertise that largely resides within the Biochemistry Department.”
The spirit of collaboration continues. Last year, the facility worked with 51 principal investigators from 23 different departments.
Dr. Posner conducted postdoctoral research in the lab of the late Dr. Alfred Gilman, a 1994 Nobel Laureate as well as former Dean of the UT Southwestern Medical School and Chair of Pharmacology. Dr. Posner was a senior scientist and principal investigator in the High-Throughput Screening Center of Emphasis at Pfizer Inc. before returning to UTSW in 2009.
“I was in industry for a number of years and decided I wanted to go back to my roots in academia and help advance higher-risk screens inspired by basic research that could ultimately lead to cutting-edge therapeutics,” Dr. Posner says.
In addition to full-file and subset screening of its diverse, drug-like compound library, the HTS Core provides support in dose-response studies, secondary activity profiling, and hit-to-lead optimization in collaboration with the Medicinal Chemistry Core, led by Dr. Joseph Ready, and the Preclinical Pharmacology Core, led by Dr. Noelle Williams. Both are Professors of Biochemistry.
The HTS Core’s siRNA library was recently supplemented with the addition of an arrayed CRISPR gene-editing library.
“This library allows a researcher to selectively knock out individual genes within a cancer cell and then assess the role of that gene in tumor formation, growth, and progression,” Dr. Posner says. “This information is invaluable in understanding cancer cell biology and also in understanding the mechanism of action by which a small molecule targets the cancer.”
During its existence, the HTS Core has performed more than 250 screening projects, resulting in 109 scientific publications, over 107 grants, and 14 licenses to 10 companies.
“This library allows a researcher to selectively knock out individual genes within a cancer cell and then assess the role of that gene in tumor formation, growth, and progression.”
In one of those UT Southwestern projects, Dr. Margaret Phillips, Chair of Biochemistry, is involved in an international partnership to develop treatments for malaria. Other partners include the University of Washington, Monash University in Australia, and Medicines for Malaria Venture.
“We found our lead molecule in a screen of the UTSW compound library using our HTS Core and, after subsequent lead optimization, identified a compound [DSM265] in 2009 that is currently in phase two clinical trials for the treatment of malaria,” says Dr. Phillips, who is also a Professor of Pharmacology. “The initial screen was performed in 2003. The clinical candidate was identified in December 2009, and its structure was first published in 2011.”
While the HTS Core does some fee-for-service work, the majority of its projects are campus collaborations. Dr. Posner provides approval for smaller projects, while the Cancer Center HTS Oversight Committee reviews proposals for larger studies. Process details are on the . The facility can also accept projects from other universities and academic medical centers, he says.
Large or small, all projects begin with a conversation in Dr. Posner’s office.
“The people in our group have several years to decades of experience in screening, so all an investigator needs to do is come and talk to us about their idea and we can help them formulate a screening strategy,” Dr. Posner says.
“We really enjoy working in this environment. It’s very collaborative at UT Southwestern and that makes our job exciting and fun.”
The HTS Core is supported through funding from the Simmons Cancer Center, the Cancer Prevention and Research Institute of Texas, the National Cancer Institute, and UT Southwestern.
Dr. McKnight, a Professor of Biochemistry, holds the Distinguished Chair in Basic Biomedical Research.
Dr. Phillips holds The Sam G. Winstead and F. Andrew Bell Distinguished Chair in Biochemistry.
Dr. Ready holds the Bonnie Bell Harding Professorship in Biochemistry.