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Synthetic chemistry core: Improving potency, stability, safety

Dr. Joseph Ready examines a flask of liquid.
Dr. Joseph Ready

Across UT Southwestern, ongoing collaborations in medicinal chemistry strive to improve the potency, selectivity, stability, and safety of biologically active small molecules.

To these ends, the Synthetic Chemistry Core’s faculty and staff work closely with the Preclinical Pharmacology Core, directed by [Professor of Biochemistry] Dr. Noelle Williams, as well as the High-Throughput Screening (HTS) facility while also providing consultation and general advice on drug discovery and development.

“We’re a synthetic and medicinal chemistry research lab,” says Dr. Joseph Ready, Professor of Biochemistry. “We work with biologists from across campus who have run high-throughput screens at the HTS facility that [Professor of Biochemistry] Dr. Bruce Posner’s group runs.

“Most current drug discovery efforts focus on a specific gene or protein and look for ways to influence them with small molecules. By contrast, we started with the small molecule and then worked backward to find its protein target.”

Dr. Deepak Nijhawan

“At the Synthetic Chemistry Core, we often work with biologists to take those early compounds [found in the HTS Core] and try to improve them to make them suitable for testing in cells or in their animal models.”

Synthetic chemists work to create new derivatives of drug-like molecules with useful biological properties. The collaborative design and preparation of these new biomedically applicable compounds can eventually lead to discoveries in pharmaceuticals, materials, detection, energy utilization and storage, and further insights into biological systems. Synthesis of new catalysts can also uncover more efficient ways to mass-produce the compounds and to prepare new variants.

UT Southwestern recruited Dr. Ready to the faculty in 2003 after his doctoral education in chemistry at Harvard University and postdoc work at Yale. Here, his investigations focus on the synthesis of biologically active small molecules – especially complex anti-cancer agents – from marine and bacterial sources. His lab also focuses on producing synthetic compounds discovered via high-throughput screening.

“We’ve worked with UT Southwestern research groups to try to develop molecules activated inside tumors to kill cancer cells in a way that does not kill healthy tissues,” says Dr. Ready, a Southwestern Medical Foundation Scholar in Biomedical Research who holds the Bonnie Bell Harding Professorship in Biochemistry. “Selective activation of a drug within a tumor would ultimately result in better therapeutic outcomes.”

Dr. Deepak Nijhawan
Dr. Deepak Nijhawan

One collaboration that has proved particularly fruitful involves Dr. Deepak Nijhawan’s award-winning work to identify targets for cancer treatment using two compounds called indisulam and CD437. Although identified as anti-cancer agents in the 1990s, these molecules were only developed recently because their targets were poorly understood. In 2016, however, Dr. Nijhawan’s group identified the protein target of CD437, and the next year identified the target of indisulam and of cancer-cell variants most susceptible to its effects.

“We took an ‘old-fashioned’ and now uncommon approach to cancer drug discovery,” says Dr. Nijhawan, Assistant Professor in the Departments of Internal Medicine and Biochemistry and a physician-scientist who graduated in 2005 from UTSW’s Medical Scientist Training Program, which confers dual M.D./Ph.D. degrees.

“Most current drug discovery efforts focus on a specific gene or protein and look for ways to influence them with small molecules. By contrast, we started with the small molecule and then worked backward to find its protein target. By uncovering indisulam’s and CD437’s targets, we have revitalized the effort to develop them into potential therapeutics.”

The Nijhawan group has since partnered with Peloton Therapeutics to further investigate the indisulam discoveries and with the Harrington Discovery Institute to develop CD437 into a cancer therapeutic. Dr. Steven McKnight, Professor of Biochemistry and holder of the Distinguished Chair in Basic Biomedical Research, is the Scientific Founder and Chairman of Peloton’s Scientific Advisory Board.

The significance of these laboratory advances and oncological applications led the American Society for Clinical Investigation (ASCI) – a prestigious group of physician-scientists – to recognize Dr. Nijhawan in April as a co-winner of the 2018 Donald Seldin-Holly Smith Award for Pioneering Research. That honor bears the names of two iconic figures in U.S. medicine – the late Dr. Donald Seldin of UT Southwestern and Dr. Lloyd “Holly” Smith Jr. of the University of California, San Francisco. Dr. Nijhawan shared the ASCI award with Harvard Medical School Assistant Professor Dr. Anna Greka, who focuses on developing targeted treatments for kidney diseases.