About Dr. Dennis Liotta

In his decades-long career at Emory University, Dr. Dennis Liotta has drastically improved the longevity and quality of life of millions worldwide. These impressive accomplishments are not limited to just one significant discovery, as he has been directly involved in the discovery and development of multiple life-saving therapeutic agents. As a successful entrepreneur and visionary leader, he has created or fostered many businesses in the biotech and pharmaceutical industry. He has also pioneered new approaches to drug development in academia. All these achievements attest to his exceptional contributions to improving human health.

Education, Training, and Academic Positions

Dr. Liotta obtained his B.S. degree in chemistry from Queens College in 1970 and his Ph.D. degree in organic chemistry from the City University of New York in 1974. He then carried out postdoctoral research at the Ohio State University.

In 1976, Dr. Liotta joined Emory University as an assistant professor. He was promoted to full professor in 1988 and currently holds the Samuel Candler Dobbs Professorship. He served as the Chair of the Chemistry Department from 1993 to 1996 and Emory’s Vice President for Research from 1996 to 2000. In 2011, he was honored with the Thomas Jefferson Award, Emory University’s highest service award.

Achievements in Drug Discovery Research

Dr. Liotta is a world-renowned medicinal chemist and an innovator in drug discovery. His research focuses on the discovery and development of novel antiviral, anticancer, and anti-inflammatory therapeutic agents. To date, he has authored more than 300 peer-reviewed publications, cited by scientists around the globe tens of thousands of times. These publications fundamentally shaped modern medicinal chemistry and profoundly influenced countless young researchers.

Dr. Liotta holds inventorship to over 100 issued patents in the U.S. alone and has more than 20 patent families currently under prosecution. He is the recipient of the 2022 Perkin Medal, generally considered to be the highest award for achievements in applied chemistry. He was elected to the National Academy of Inventors in 2014 and the Medicinal Chemistry Hall of Fame in 2010.

Dr. Liotta’s innovations have resulted in 18 life-saving FDA-approved antiviral therapeutics. These include Atripla®, Biktarvy®, Combivir®, Complera®, Delstrigo®, Descovy®, Dutrebis®, Emtriva®, Epivir®, Epivir-HBV®, Epzicom®, Genvoya®, Odefesey®, Stribild®, Symtuza®, Triumeq®, Trizivir®, and Truvada®.

Antivirals

Dr. Liotta has helped transform HIV/AIDS from a death sentence to a chronic infection in which patients can live active and productive lives. The Emory University Office of Technology Transfer estimates that about 95% of the people living with HIV/AIDS in the U.S., and many around the world, take or have taken one of the drugs co-invented by Dr. Liotta.

Dr. Liotta is most noted for his invention of emtricitabine and lamivudine, along with Drs. Raymond Schinazi and Woo-Baeg Choi. These two drugs are widely used as crucial components of anti-HIV combination therapies. They played instrumental roles in combating the HIV/AIDS epidemic in the U.S. and curbing the spread of HIV in other regions of the world. Millions of HIV/AIDS patients can live long and near-normal lives because of the discovery of emtricitabine and lamivudine. Emtricitabine, marketed under the name Emtriva®, made possible the first-ever combination therapy for HIV/AIDS as a once-daily pill. It is a component of many combination therapies used to treat HIV/AIDS, including Truvada®, Atripla®, Complera®, Stribild®, Genvoya®, Odefesey®, Biktarvy®, Descovy®, and Symtuza®. In addition to its use as a therapeutic, emtricitabine is also used in combination with other antivirals to protect healthy individuals from acquiring HIV – known as Pre-Exposure Prophylaxis or PrEP. Lamivudine, marketed under the name Epivir®, is a component of multiple combination therapies such as Combivir®, Trizivir®, Epzicom®, Triumeq®, Dutrebis®, and Delstrigo®. Notably, lamivudine also became the first drug approved by the FDA to treat hepatitis B infections. Both emtricitabine and lamivudine are on the World Health Organization’s List of Essential Medicines.

Other Therapeutic Areas

While Dr. Liotta’s most significant impact has come from the HIV/AIDS therapeutics, he has also made important contributions to other therapeutic fronts, such as oncology and neurological diseases. He co-discovered samuraciclib (formerly CT7001), a CDK7 inhibitor for treating hard-to-treat cancers. Samuraciclib is in Phase 2 clinical trials and has been fast-tracked by the FDA for use in two combination therapies to treat certain breast cancers. He also developed Q-122, an oral drug for controlling hot flashes in postmenopausal women, which has completed a Phase 2 clinical trial. In addition, his collaboration with Dr. Stephen Traynelis in Emory’s Department of Pharmacology and Chemical Biology laid the foundation for the discovery of NP-10679. NP-10679 successfully wrapped up its Phase 1 clinical trial and has received Orphan Drug designation from the FDA for treating subarachnoid hemorrhage or bleeding in the space around the brain.

Successes in Technology Transfer and Entrepreneurship

Dr. Liotta catalyzed more than 30 license agreements between Emory University and various commercialization partners, including at least 25 exclusive license agreements and seven non-exclusive license agreements. Through these license deals, many therapeutic agents developed in Dr. Liotta’s laboratory were advanced to the clinic and beyond by the commercialization partners.

As a serial entrepreneur, Dr. Liotta co-founded more than ten biotech companies, including Altesa Biosciences, AgriThera, Que Oncology, NeurOp, Pharmasset, Altiris Therapeutics, Triangle Pharmaceuticals, Metastatix, FOB Synthesis and iThemba Pharmaceuticals. These businesses fostered economic growth, created numerous jobs in the biotechnology sector, and brought multiple drugs to the marketplace. One prominent example among these companies is Pharmasset, which developed sofosbuvir (Sovaldi®), a blockbuster, curative hepatitis C medicine. Pharmasset was acquired by Gilead Sciences for $11.2 billion in 2012. Another notable example is Triangle Pharmaceuticals, which advanced emtricitabine through its Phase 3 clinical trials before being acquired by Gilead Sciences for $525.2 million in 2003.

Dr. Liotta is currently serving or previously served on the Scientific Advisory Boards of more than a dozen biotech companies and venture capital firms. His knowledge of medicinal chemistry and experience in drug discovery and development have provided critical support to these companies’ technological advancement and commercial growth.

Innovation in Academic Drug Development and the DRIVE Model

Dr. Liotta is dedicated to innovating new approaches to drug development in academia. He aims to overcome many intrinsic (and often unforeseen) barriers associated with academic drug development, such as inadequate infrastructure, insufficient expertise and lack of translational funding.

He and fellow drug developer, Dr. George Painter, set up an innovative model a decade ago to bolster academic drug development infrastructure and provide critical resources in the developmental continuum for new therapeutics. In 2009-12, Dr. Liotta funded the creation of a pair of complementary entities at Emory University – Emory Institute for Drug Development (EIDD) and Drug Innovation Ventures at Emory (DRIVE). These two entities form a strategic alliance to advance drug development at Emory, one of the first of its kind in the nation. The EIDD, equipped with state-of-the-art facilities and highly trained research personnel, serves as an engine for early-stage research and development. DRIVE, staffed by an experienced leadership team having critical expertise in business development, intellectual property law, and pre-clinical and clinical research, acts as a commercialization partner to advance drug candidates to subsequent value inflection points. Revenues generated from out-licensing the pre-clinical and clinical assets are channeled back to EIDD and DRIVE to fund new drug discovery campaigns.

Without shareholders or investors, EIDD and DRIVE strive to address the most critical unmet medical needs rather than pursue markets with the highest profit margins like their commercial sector counterparts. For example, EIDD and DRIVE focus on developing therapeutics for viral diseases of global concern. Many of these diseases had not been commercially viable targets for large pharmaceutical companies or privately held biotech companies.

Over the years, the DRIVE model has generated successes across multiple research fronts. For instance, the EIDD won several multi-million-dollar government contracts in antiviral drug discovery. The EIDD and DRIVE also developed many promising antiviral agents, some of which were subsequently out-licensed to commercialization partners. One example is ATI-2173 (formerly EIDD-2173), a novel, orally available antiviral agent that can potentially provide a cure for hepatitis B. ATI-2173 is out-licensed to Antios Therapeutics, which recently raised $96 million in Series B financing to fund its Phase 2 clinical trials. Aside from antiviral agents, the EIDD also worked on various other therapeutic areas. For example, it discovered NTS-104 (formerly EIDD-1723), a novel neurosteroid prodrug for treating stroke and traumatic brain injuries. NTS-104 is licensed to NeuroTrauma Sciences and is poised to enter clinical trials in the last quarter of 2022.

The EIDD and DRIVE’s efforts to develop therapeutics for commercially neglected diseases unexpectedly provided a critical advancement against the COVID-19 pandemic. Molnupiravir (formerly EIDD-2801), a broad-spectrum antiviral agent initially developed by EIDD and DRIVE for addressing multiple single-stranded RNA virus infections, provided a pivotal solution for COVID-19 treatment. Now licensed to Merck, this drug is currently one of only two oral medications granted Emergency Use Authorization by the FDA for treating SARS-CoV-2 infections. To date, Merck has supplied molnupiravir to more than 25 countries, including the U.S., which purchased 3.1 million treatment courses ($2.2 billion). The New York Times reported this exciting story. It commented, “in the race for a COVID-19 pill, a little lab [at Emory] plays a big role.”

Dr. Liotta documented the DRIVE model in an article published in ACS Medicinal Chemistry Letters. This model will serve as a practical guide for restructuring academic drug development among other universities and research institutions. Without resting on the success of the DRIVE model, Dr. Liotta is currently working on a new initiative to strategically expand the therapeutic scope of the EIDD/DRIVE and implement operational capacity to make this platform available to a broader scientific community at Emory University.

Contributions to Cultivating the Next Generation of Scientists and Innovators

In addition to scientific research and innovations, Dr. Liotta values the power of teaching and mentorship. The training and education of students and junior scientists is an essential component of Dr. Liotta’s career. His laboratory has a strong track record in cultivating the next generation of scientists and innovators. To date, he has mentored and supervised nearly 300 undergraduate and graduate students, postdoctoral fellows, research scientists, and visiting scholars – including ~100 undergraduate students, ~100 graduate students, and ~70 post-graduates.

Dr. Liotta always encourages his students and mentees to think independently. He generously provides them with abundant resources for their research projects and career development. Many alumni from his laboratory have successful careers in a wide array of sectors, including academia, the biotech and pharmaceutical industry, intellectual property law and technology transfer.

Global Impact

As a caring humanitarian, Dr. Liotta has devoted incredible efforts to improving human health worldwide, especially in underserved regions. Over the past twenty years, he initiated a series of outreach activities to cultivate the next generation of African scientists, implementing unique mechanisms to provide them with the scientific skills and business acumen required to address African healthcare needs.

In 2008, Dr. Liotta started iThemba Pharmaceuticals, a South African biotech firm focusing on developing medicines to treat diseases hitting Africa the hardest, such as HIV, tuberculosis and malaria. The company operated under a unique business model: it started out by pursuing contract research work in medicinal chemistry, such as custom synthesis and scale-up synthesis, the revenue from which was then utilized to fund its internal drug discovery efforts. Although a lapse in funding from the South African government led to the shutdown of iThemba Pharmaceuticals, it cultivated many talents in Africa and helped lay the foundation from which a biotechnology industry can grow.

The most recent iteration of Dr. Liotta’s African outreach activities involves an initiative called AHIA (Advancing Healthcare Innovation in Africa). AHIA’s mission is to support and promote the advancement of health innovation and health-related technologies in Africa by advising, educating, and training African scientists in the business and legal aspects of the biotech and pharmaceutical sector. The initiative seeks to address the unique challenges of building Africa’s innovation capacity in drug discovery and development by creating platforms for identifying promising new local technologies, advancing the human capital needed to further those technologies through mentoring and education, and translating the technologies from laboratories to clinics and markets.

Services to the Scientific Community

Dr. Liotta is the founding Editor-in-Chief of ACS Medicinal Chemistry Letters (ACS MCL), which was launched in 2010 to provide a rapid communication venue for high-quality letters and technology notes in medicinal chemistry and related fields. Under his leadership, ACS MCL has become one of the preeminent journals for disseminating innovative medicinal chemistry reports. Additionally, he serves as a Fellow of both the American Association for the Advancement of Science and the American Chemical Society.

Dr. Liotta embodies all of the finest qualities of a true leader dedicated to improving human health through exceptional and original research in medicinal chemistry. In addition to his excellent scholarship, he is an extraordinary inventor, innovator, entrepreneur, and leader. What differentiates Dr. Liotta from his peers is his ability to meld his scientific prowess with business acumen and intellectual property awareness, his dedication to innovating new approaches to drug development in academia and his lasting commitment to educating the next generation of scientists and innovators in the U.S. and the developing world.

CXCR4

Oncogenic and Immunosuppressive Mechanisms of CXCR4

CXCR4 (CXC chemokine receptor 4) is a seven transmembrane G protein-coupled chemokine receptor. Its only endogenous ligand is CXCL12 (CXC chemokine ligand 12, also known as stromal cell-derived factor 1 (SDF-1)). CXCL12 regulates the trafficking of CXCR4+ leukocytes and hematopoetic stem cells under normal physiological conditions (homeostasis). CXCR4 is expressed in T cells, neutrophils, mast cells, eosinophils, basophils, B cells, monocytes/macrophages, dendritic cells, endothelial cells. CXCR4 also plays a crucial role in pathological conditions, such as cancer, HIV/AIDS, and autoimmune diseases.

 

CXCR4 and CXCL12 stimulate proliferation and migration of hematopoietic stem cells (HSCs) and lineages. The overexpression of CXCR4 on > 48 cancer cell types confers:

  • Pro-survival gene transcription in the primary tumor microenvironment
  • Pro-angiogenic and pro-vasculogenic cytokine expression promoting tumor progression and CXCR4+ cancer cell access to systemic circulation
  • Immunosuppressive and chemo-resistant adhesion to and migration beneath tumor-associated stroma

 

CXCR4 and CXCL12 are independent indicators of poor clinical prognosis for patients suffering from various types of cancer

Oncotarget, Vol 6, No. 7, 2014, 5022-5040.

CXCR4 ANTAGONISTS CAN INHIBIT CANCER PROGRESSION BY:

  • Disrupting tumor-associated stromal interactions that confer tumor cell survival and drug resistance
  • Blocking the autocrine and paracrine growth and survival signals through activation of the CXCR4/CXCL12 axis
  • Hindering tumor cell metastasis and homing to distant CXCL12-rich stromal niches
  • Tumor cell mobilization from CXCL12-rich tissue to increase chemotherapeutic accessibility
  • Obstructing CXCL12-mediated recruitment of pro-vasculogenic and pro-angiogenic CXCR4+ bone marrow-derived progenitor cells

CXCR4 inhibitors can also recondition the leukocyte infiltrate of the tumor microenvironment in an immunomodulatory manner that induces a higher susceptibility to the host immune system.

The evolution of our tetrahydroisoquinoline-based CXCR4 antagonists led to the discovery of a clinical candidate and several backup compounds, which have been selected for further development. The in vitro activity profiles of these compounds are shown below. Most notably, clinical candidate EMU-000116 demonstrates superiority over X4P-001, which is currently undergoing Phase 2 and Phase 3 clinical evaluation. As highlighted in the table, EMU-000116 outperforms X4P-001 in human liver microsomal stability assays, PAMPA permeability assays, and aqueous solubility assays. EMU-000116 also exhibits a much more attractive therapeutic index, as indicated by the ratio of cAMP IC90 values to hERG IC20 values.

Activity Profiles of Clinical Candidate and BackupsExperiments performed by Bristol-Myers Squibb and by Dr. Savita Sharma in the Liotta Group at Emory University

These top CXCR4 antagonists were further evaluated for plasma pharmacokinetic and tissue distribution properties in mice after single and multiple oral doses, respectively. Building upon the in vitro activity profiles, clinical candidate EMU-000116 and clinical backups EMU-000161 and EMU-000232 demonstrated substantially improved plasma t1/2 values in vivo, as well as impressively enhanced oral absorption and bioavailability, relative to X4P-001. These compounds additionally achieved significantly elevated concentrations in mouse liver, lung, kidney, heart, and bone marrow after oral administration. Notably cAMP IC90 values were robustly covered in these tissues, and heart concentrations did not exceed hERG IC20 values.

CXCR4 Antagonist Mouse Plasma Pharmacokinetic Profiles (p.o.)3 Male ICR mice per treatment group received a single dose i.v. (3 mg/kg) or p.o. (3, 10, or 30 mg/kg); Vehicle = 45:10:45 Kolliphor:DMA:PBS; Data represents mean [compound] ± SEM; Experiments arranged by Dr. Yi Jiang and performed by Dr. Yan Dai and colleagues at Shanghai Sundia Co., Ltd.

Top CXCR4 Antagonist Mouse Tissue DistributionMice dosed by Dr. Carrie Sun in the Petros Lab @ Emory Urology; Tissue harvest conducted by Dr. Carrie Sun, Dr. Edgars Jecs, and Dr. Eric Miller in the Petros Lab @ Emory Urology; LC-MS/MS analysis of drug concentrations performed by Zack Sticher @ EIDD

To examine whether these improved pharmacokinetic properties would translate to improved efficacy, EMU-000116 was compared head-to-head to X4P-001 in a mouse xenograft model of renal cell carcinoma. In combination with axitinib, 3 mg/kg and 10 mg/kg EMU-000116 was equally effective as 100 mg/kg X4P-001 at combating tumor growth. Furthermore, 30 mg/kg EMU-000116 not only statistically significantly demonstrated superior anti-tumor efficacy relative to 100 mg/kg X4P-001, but tumor size was actually reduced under this therapeutic paradigm. Notably, none of the dosing regimens caused systemic toxicity, as indicated by the lack of changes in body weight over time.

Superior Anti-Tumor Activity in RCC Mouse Xenograft Model

  • Female nude mice (n = 10 per treatment group) received 786-0 renal cell adenocarcinoma tumors s.c.
  • Once daily dosing via oral gavage for 21 days (Vehicle = 45:10:45 Kolliphor:DMA:PBS)
  • Tumor volume measured with calipers, and data represents the mean tumor volume, mean change in body weight, or mean tumor weight ± SEMExperiments arranged by Dr. Yi Jiang and performed by Dr. Yan Dai and colleagues at Shanghai Sundia Co., Ltd.

The conclusion from this experiment is that EMU-000116 boosted the anti-angiogenesis effects of axitinib better and at a lower dose than X4P-001.

NMDA Receptor Modulators

N-Methyl-D-Aspartate (NMDA) Receptors

The NMDA receptor belongs to the ionotropic glutamate receptor family and is responsible for mediating excitatory neurotransmission in the central nervous system. It is a heterotetramer, made up of two glycine-binding GluN1 subunits with 8 splice variants and two glutamate-binding GluN2 subunits with 4 subtypes (2A to D), which render the receptor with different expression patterns in the brain. This ligand-gated ion channel is permeable to Ca2+, Na+ and K+ ions and has a voltage dependent Mg2+ block.

The NMDA receptor is critical for nearly every function of the brain and is involved in learning, memory, brain development and synaptic plasticity. NMDA receptor dysfunction has been implicated in numerous neurological disorders, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, schizophrenia and depression.

In Vivo characterization of NMDA Modulators for Analgesic Tolerance

Drug overdose is the leading cause of accidental death in US, with 60% of cases due to chronic opioid use.
Analgesic Tolerance refers to a decreased response to analgesic effects of opioids, requiring higher doses to achieve desired effect. The over-activation of NMDARs has been implicated in development of tolerance.

Our research in this field aim to answer the following:

  • Can our novel NMDAR modulators elicit analgesia on their own?
  • What effect do they have on development of analgesic tolerance?
  • What is the effect of pH boost?
  • Can our modulators potentiate the anti-nociceptive effects of morphine (leftward shift in morphine dose-response curve with addition of compound)?
  • Can our modulators reverse tolerance once it has been established?
  • Do they adversely affect learning and/or memory?

RSV

Human Respiratory Syncytial Virus (RSV) Inhibitors

RSV is an enveloped, non-segmented, negative-strand RNA virus and the global leading cause of viral-related upper and lower respiratory illness in the elderly, infants and children < 5 years. In the USA, RSV hospitalizes more than 57,000 children < 5 years and about 177,000 elderly patients annually. An estimated 14,000 elderly patients die from RSV each year. Current therapeutic and prophylactic options are limited, expensive and unreliable.

Our research efforts involve two target viral proteins:

1. RSV Fusion Protein
Popular therapeutic strategy involves targeting the RSV fusion (F) protein which is critical for viral fusion with the targeted host cell membrane.

2. RSV Nucleoprotein

Another strategy involves targeting the nucleoprotein (N) which is essential for viral assembly and replication. This area has been well researched by other groups, using benzodiazepine scaffolds and have generated a wealth of SAR information for further optimization.