Tuesday, October 10, 2023, 11:30 AM – 1 PM EDT

Novel Therapeutics for Treating Viral Diseases, Cancer and Neurological Disorders

Dennis Liotta, PhD, DSC -- Emory University Department of Chemistry
 

Led by Dr. Dennis Liotta, the Liotta Research Group (LRG) is a complex medicinal chemistry organization within Emory University. This talk will start with an overview of the LRG’s earlier success in the antiviral arena and transition into LGR’s recent endeavors in (1) developing novel CXCR4 antagonists as immunomodulators for treating cancer and (2) designing fast-release neurosteroid prodrugs for treating traumatic brain injury.

Part I. CXCR4 antagonists – Pro-angiogenic and immune cells expressing chemokine receptor CXCR4 traffic along concentration gradients of its chemokine ligand CXCL12, which disseminates from stromal niches in lymph nodes, lung, liver, and bone marrow. The CXCR4/CXCL12 axis is hijacked by numerous cancer types characterized by dramatic CXCR4 and/or CXCL12 upregulation. Consequently, CXCR4 antagonists have significant therapeutic potential against cancer progression. In the past decade, the LRG has designed, synthesized, and evaluated over 350 tetrahydroisoquinoline-containing CXCR4 antagonists. Leading this pipeline is EMU-116, which exhibited enhanced pharmacokinetic properties and superior anti-tumor efficacy compared to mavorixafor, a small molecule CXCR4 antagonist studied in clinical trials. Ultimately, our CXCR4 antagonist pipeline has significant potential to deliver the best-in-class CXCR4 antagonist for treating a variety of cancers.

Part II. Neurosteroid prodrugs – Despite tremendous amount of scientific effort allocated towards the development of pharmacological interventions for reducing the impact of traumatic brain injury (TBI) on public health, none have resulted in an FDA-approved neuroprotective agent. In recent years, neurosteroids, such as progesterone, emerged as promising neuroprotective agents for treating TBI. Unfortunately, previous investigations into the use of neurosteroids for TBI treatment typically required administration in a hospital setting, thus losing valuable time before the treatment could be administered. To address this unmet need, the LRG has developed two generations of progesterone prodrugs having improved aqueous solubility and fast in vivo release rate. Their efficacy was demonstrated in a rat model of acute TBI.