Scientific Advisory Board

Paul Boehmer, PhD
Interim Associate Dean for Research and Professor

Scott Boitano, PhD
Professor, Physiology
Professor, Cellular and Molecular Medicine
Professor, BIO5 Institute
Professor, Physiological Sciences
Research Scientist, Asthma and Airway Disease Research Center

Scott Boitano has been associated with the University of Arizona since he moved to Tucson in 2002. He established research in lung toxicology and drug development targeting the protease activated receptor-2 (a G protein-coupled receptor that is expressed in the airway epithelium, where it participates in exacerbations of allergic asthma. It is also expressed in nociceptors (pain sensing neurons), where it participates in pain pathways).

At the University of Arizona, Dr. Boitano has been part of a collaboration with Drs. Theodore J. Price and Josef Vagner that has developed the most potent agonists and the only antagonist that can block all signaling pathways activated by proteases. Current interests include the further development of agonists and antagonists into drugs that can be used in the control of asthma and pain.


Ali Bridges, MPA, BA
Director of Communications

Ali Bridges obtained her Bachelor of Arts in Journalism from the University of Georgia and is expected to earn her Master of Public Affairs from the University of Missouri by August 2020. Her career in marketing and PR has covered a variety of areas from copywriting and publicity, to media relations and crisis communications. Prior to taking on the role of Director of Communications at the University of Arizona's College of Pharmacy, she managed marketing and brand strategy for Valdosta State University, working to promote over 100+ programs, and develop and moderate the university's brand platform.

Ali is originally from Atlanta, GA. 

 


Rakhi Gibbons, MSB
Director, Licensing
Tech Launch Arizona

Rakhi Gibbons has over fifteen years of experience in the life sciences industry from research to startup experience to university technology transfer. She oversees all licensing operations for Tech Launch Arizona. In her position as Director, she has worked closely with faculty and researchers particularly in the Arizona Health Sciences Center, and life sciences departments across the university overseeing intellectual property.

Prior to joining the University of Arizona, she served on the licensing team in the University of Michigan’s Office of Technology Transfer. Rakhi has substantial experience in intellectual property, licensing, technology and contracts management, conflict of interest, and start up formation. In addition to her background in business, she has practical knowledge of life sciences through research with a biotech company in northern California, and Stanford University in the areas of molecular biology and genomics.


Andrew S. Kraft, MD
Professor, Medicine
Associated Vice President, Oncology Programs
Professor of Cell and Molecular Medicine
Senior Associate Dean for Translational Research

Andrew S. Kraft, MD, is the Sydney E. Salmon endowed chair and serves as associate vice president for oncology programs for the UA Health Sciences Center; professor of medicine in the Department of Medicine’s hematology/oncology section; and senior associate dean for translational research in the College of Medicine. Dr. Kraft received his medical degree from the University of Pennsylvania and did his residency in internal medicine at Mount Sinai Hospital in New York. He then served as a research assistant and then as a clinical staff fellow at the National Cancer Institute (NCI). After 13 years with the University of Alabama – Birmingham, he spent eight years at the University of Colorado Health Sciences Center, before being recruited to the Medical University of South Carolina in 2004. Dr. Kraft led the Hollings Cancer Center at the Medical University of South Carolina to become an NCI-designated cancer center with more than $42 million of annual research projects. He and his wife Katharine, a retired social worker, have three adult children living in the Denver area, near San Francisco and in Minneapolis. For 40 years, Dr. Kraft has enjoyed spending his free time as a sculptor, creating what he calls anthropomorphic statues, and life-size heads made in clay. He then casts them in various media, such as plaster or cement, or sends them to a foundry to be cast in bronze.


William Montfort, PhD
Therapeutic Development Program co-Leader
Therapeutic Development Program, Research Member
Professor, Chemistry and Biochemistry-Sci
Professor, BIO5 Institute
Professor, Molecular and Cellular Biology
Professor, Applied Mathematics - GIDP
Professor, Cancer Biology - GIDP
Professor, Genetics - GIDP

Jon T. Njardarson, PhD
Professor, Chemistry & Biochemistry

Jón was born and raised in the small town of Akranes, Iceland. After graduation, he left his hometown and moved to Reykjavik to start his studies at the University of Iceland. During his first year at the University he became fascinated by the wonders of Organic Chemistry, which has continued ever since. As an undergraduate, Jon worked in the laboratory of Professor Jon K. F. Geirsson on the synthesis of antifungal agents. After graduation, he worked at the University of Iceland Science Institute in addition to serving as a teaching assistant at the University. Jon then followed in the footsteps of his Icelandic ancestors and moved west, to America. This journey brought him to New Haven Connecticut, where he chose to pursue a graduate career in Organic Chemistry at Yale University. While at Yale, he joined the research group of a newly hired assistant professor, John L. Wood, after becoming affected by his enthusiasm, energy and exciting new research program. During his doctoral studies Jon worked on the total synthesis of the nonadride natural products CP-225,917 CP-263,114. At the end of his graduate studies Jon was presented with the irresistible offer of moving to New York City to work in the laboratory of Professor Samuel J. Danishefsky the Memorial Sloan-Kettering Cancer Center (MSKCC). While in the Danishefsky group, as a General Motors Cancer Research Scholar, he worked on the total syntheses of the natural products epothilone 490 and migrastatin. Jon moved to Ithaca in 2004 to start his independent career at Cornell University, where he launched a research program focused on natural products and the development of new methods. In 2010 Jon and his group loaded the wagons, journeyed across the continent, and settled in Tucson where he is a professor in the Department of Chemistry and Biochemistry at the University of Arizona.


Rick Schnellmann, PhD
Dean, College of Pharmacy
National Advisory Board Member
Howard J. Schaeffer Endowed Chair in Pharmaceutical Sciences
Professor

Rick G. Schnellmann, PhD, is dean of the University of Arizona College of Pharmacy. A leading pharmacologist, researcher and drug discovery entrepreneur, he joined the UA in August 2016. Dr. Schnellmann earned his doctorate in pharmacology and toxicology from the University of Arizona College of Pharmacy and Medicine in 1984. Previously, Dr. Schnellmann worked at the South Carolina College of Pharmacy at the Medical University of South Carolina (MUSC) in Charleston, where he was an eminent scholar and distinguished university professor and was chair of the college's Department of Drug Discovery and Biomedical Sciences from 2001 to 2015. Under his guidance, his department's NIH grant funding increased, and in 2014 the school was ranked 11th in NIH funding among colleges of pharmacy. Dr. Schnellmann's research is focused on identifying and developing drugs to treat acute kidney injury, diabetic kidney disease, stroke, spinal cord injury and Parkinson's disease. His research has been funded continuously since 1987 and includes NIH grant funding totaling more than $30 million. He has been instrumental in founding three MUSC spin-off biotechnology companies focused on drug discovery and development. 


Rachna Shroff, MD, MS
Chief, Section of GI Medical Oncology
Chair, Data Safety Monitoring Board
Leader, GI Disease-Oriented Team
Associate Professor, Hematology/Oncology (College of Medicine)

Rachna T. Shroff, MD, MS is an Associate Professor in the Department of Medicine, Division of Hematology and Oncology, Chief of the Section of GI Medical Oncology.

Dr. Shroff has been a member of the ASCO Scientific Committee, Noncolorectal Track as well as the ASCO Gastrointestinal Guidelines Advisory Group. She participates in the Southwest Oncology Group (SWOG) GI Committee, and the NCI Hepatobiliary Taskforce being the national Principal Investigator on SWOG 1815. She is also involved in the International Cholangiocarcinoma Research Network (ICRN) where she participates in the Novel Targets Working Group.

Dr. Shroff completed her fellowship in medical oncology at the University of Texas MD Anderson Cancer Center. She simultaneously obtained a Master's Degree at the University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences. She did her residency in internal medicine at Washington University in St. Louis where she also served as Chief Resident at the VA Hospital. Dr. Shroff earned her medical degree from Jefferson Medical College in Philadelphia.


Joann Sweasy, PhD
Interim Director, Cancer Center Division
Associate Director, Basic Sciences
Professor, Cellular and Molecular Medicine

Dr. Sweasy earned her doctoral degree from Rutgers University, studying the role of the RecA protein in the SOS response to DNA damage, under the direction of Dr. Evelyn M. Witkin. She initiated her research on the fidelity of DNA synthesis at the University of Washington in Dr. Lawrence Loeb’s laboratory. After joining Yale University School of Medicine in 1993, she rose through the ranks to become the Ensign Professor of Therapeutic Radiology and Associate Director for Basic Sciences at the Yale Cancer Center. Dr. Sweasy is currently a tenured professor in Cellular and Molecular Medicine and is Associate Director, Basic Sciences at the University of Arizona Cancer Center. 

Cancer Focus

Dr. Sweasy is an internationally recognized expert the genetics, cell biology, and biochemistry of DNA repair. For the past 25 years her laboratory has been consistently funded by the National Cancer Institute to study the molecular basis of mutagenesis and dysfunctional DNA repair as they relate to human diseases including cancer and autoimmunity. Dr. Sweasy’s research team recently discovered that dynamic conformational changes are important for accurate DNA synthesis. The team has also shown that human germline and somatic genetic variants of base excision repair genes are linked to carcinogenesis because they are unable to properly remove damaged DNA bases, leading to genomic instability, mitotic catastrophe, and other cancer-associated phenotypes.


Gregory Thatcher, PhD
Professor, Pharmacology and Toxicology
R. Ken and Donna Coit Endowed Chair in Drug Discovery

Greg Thatcher, PhD, joined the University of Arizona in 2020 from the University of Illinois College of Pharmacy. In his career, he has graduated over 50 students with PhD’s and a dozen with MSc’s and mentored 40 undergraduate researchers, the majority while on faculty in the Chemistry Department at Queen's University in Canada from 1988 until 2002. These trainees have proceeded to positions in biotech, pharma, business, education, and academia in the USA, Canada, Europe, India, and China.

While at the University of Illinois in Chicago (UIC), Thatcher acted as founder/leader of the Translational Oncology Program in the University of Illinois Cancer Center and co-director of the NIA Predoctoral Training Program in Alzheimer’s Disease & Related Dementia. In 2013, he founded a campus-wide and disease-agnostic drug discovery center at UIC, focused on small molecule drug discovery, which continues to play an active role in academic drug discovery across Chicago. Dr. Thatcher created his first start-up biotech company in 1997, which successfully took an Alzheimer’s drugs into human clinical trials. Thatcher’s trainees receive a multidisciplinary education in modern aspects of medicinal chemistry, chemical biology, and chemical toxicology: the underpinning of drug discovery and development. Students who graduate with expertise in synthetic medicinal chemistry will have competency in another area, such as drug metabolism and pharmacokinetics; and students who graduate with expertise in cell/molecular biology or biochemistry will be experts in bioassay design and have competency in drug discovery.

The Thatcher lab’s research has been continuously funded by the NIH since 2003, supported by NCI, NIA, NHLBI, NIAID, and NCCAM, resulting in over 170 publications and dozens of issued patents. Two new chemical entities were licensed and successfully completed Phase 1 clinical trials for metastatic breast cancer in 2019. The first five publications listed below describe drugs that have completed Phase 1 trials:

  1. Dudek, A. Z., Liu, L. C., Fischer, J. H., Wiley, E. L., Sachdev, J. C., Bleeker, J., Hurley, R. W., Tonetti, D. A., Thatcher, G. R. J., Venuti, R. P., and O'Regan, R. M. (2020) Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine and CDK4/6 inhibitor therapy, Breast Cancer Res Treat 183, 617-627. 
  2. Andreano, K. J., Wardell, S. E., Baker, J. G., Desautels, T. K., Baldi, R., Chao, C. A., Heetderks, K. A., Bae, Y., Xiong, R., Tonetti, D. A., Gutgesell, L. M., Zhao, J., Sorrentino, J. A., Thompson, D. A., Bisi, J. E., Strum, J. C., Thatcher, G. R. J., and Norris, J. D. (2020) G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer, Breast Cancer Res Treat 180, 635-646. 
  3. Xiong, R., Zhao, J., Gutgesell, L. M., Wang, Y., Lee, S., Karumudi, B., Zhao, H., Lu, Y., Tonetti, D. A., and Thatcher, G. R. (2017) Novel Selective Estrogen Receptor Downregulators (SERDs) Developed against Treatment-Resistant Breast Cancer, J Med Chem 60, 1325-1342.   
  4. Xiong, R., Patel, H. K., Gutgesell, L. M., Zhao, J., Delgado-Rivera, L., Pham, T. N. D., Zhao, H., Carlson, K., Martin, T., Katzenellenbogen, J. A., Moore, T. W., Tonetti, D. A., and Thatcher, G. R. J. (2016) Selective Human Estrogen Receptor Partial Agonists (ShERPAs) for Tamoxifen-Resistant Breast Cancer, J Med Chem 59, 219-237.
  5. Luo, J., Lee, S. H., VandeVrede, L., Qin, Z., Piyankarage, S., Tavassoli, E., Asghodom, R. T., Ben Aissa, M., Fa, M., Arancio, O., Yue, L., Pepperberg, D. R., and Thatcher, G. R. (2015) Re-engineering a neuroprotective, clinical drug as a procognitive agent with high in vivo potency and with GABAA potentiating activity for use in dementia, BMC Neurosci 16, 67.

Research Projects

Although the Thatcher lab's greatest success has been in breast cancer; we have an opportunity to prioritize diseases of aging at UA, in particular Alzheimer’s and Related Dementia (ADRD), which is currently funded by three National Institute on Aging grants. We are also able to pivot rapidly towards health crises, such as COVID-19 (see section 8 below).

  1. In 1997 I founded a start-up with pharmacologists at Queen’s University in Canada, initially focused on small molecule neuroprotective therapeutics for ischemic stroke. This company succeeded in completing Phase 1A clinical trials in Alzheimer’s disease (AD) for a small molecule nomethiazole. This project derived from a long-standing interest in understanding the biological chemistry of nitric oxide as a basis for delivering NO in various disease states. The aim of restoring NO/cGMP/CREB signaling in the AD brain, a concept originally conceived by us, is now widely accepted. We maintain significant interest in AD addressing multiple targets in what is a multifactorial disease.  Another AD project targeted at calpain inhibitors has evolved to a focus on protecting the blood brain barrier, both activating CREB and increasing endothelial NO synthase (eNOS) may be crucial.
    1. Luo, J., Lee, S. H., VandeVrede, L., Qin, Z., Ben Aissa, M., Larson, J., Teich, A. F., Arancio, O., D'Souza, Y., Elharram, A., Koster, K., Tai, L. M., LaDu, M. J., Bennett, B. M., and Thatcher, G. R. (2016) A multifunctional therapeutic approach to disease modification in multiple familial mouse models and a novel sporadic model of Alzheimer's disease, Mol Neurodegener 11, 35.
    2. Hollas, M. A., Ben Aissa, M., Lee, S. H., Gordon-Blake, J. M., and Thatcher, G. R. J. (2019) Pharmacological manipulation of cGMP and NO/cGMP in CNS drug discovery, Nitric Oxide 82, 59-74.
    3. Schiefer, I. T., Vandevrede, L., Fa, M., Arancio, O., and Thatcher, G. R. (2012) Furoxans (1,2,5-Oxadiazole-N-Oxides) as Novel NO Mimetic Neuroprotective and Procognitive Agents, J Med Chem 55, 3076-3087.
    4. Vandevrede, L., Tavassoli, E., Luo, J., Qin, Z., Yue, L., Pepperberg, D. R., and Thatcher, G. R. J. (2014) Novel analogues of chlormethiazole are neuroprotective in four cellular models of neurodegeneration by a mechanism with variable dependence on GABAA receptor potentiation, Br J Pharmacol 171, 389-402.
    5. Qin, Z., Luo, J., VandeVrede, L., Tavassoli, E., Fa, M., Teich, A. F., Arancio, O., and Thatcher, G. R. (2012) Design and synthesis of neuroprotective methylthiazoles and modification as NO-chimeras for neurodegenerative therapy, J Med Chem 55, 6784-6801.
    6. Jastaniah, A., Gaisina, I. N., Knopp, R., and Thatcher, G. R. (2020) Synthesis of alpha-Ketoamide-based Stereoselective Calpain-1 Inhibitors as Neuroprotective Agents, ChemMedChem.
    7. Fa, M., Zhang, H., Staniszewski, A., Saeed, F., Shen, L. W., Schiefer, I. T., Siklos, M. I., Tapadar, S., Litosh, V. A., Libien, J., Petukhov, P. A., Teich, A. F., Thatcher, G. R., and Arancio, O. (2015) Novel Selective Calpain 1 Inhibitors as Potential Therapeutics in Alzheimer's Disease, J Alzheimers Dis 49, 707-721.
  2. We are currently targeting a domain of tau protein that is linked to pathogenesis of AD and other tauopathies, such as frontotemporal lobe dementia. Tau forms tangles that are one of the two hallmark pathologies of AD. In general, our AD research is not focused on AD pathology, since postmortem brains show individuals with severe pathology but no cognitive deficits at time of death. The concept of weakened neural reserve or cognitive resilience being necessary for an individual to decline to dementia, independent of pathology, has been proposed by collaborators. The contribution of traumatic brain injury (TBI) to loss of cognitive resilience with aging has also been proposed. In unpublished work, we have developed small molecule activators of the enzyme NAMPT that increase cellular NAD that is depleted with aging. We have also developed small molecules that restore cholesterol mobilization and insulin signaling, and attenuate inflammation and lipogenesis, in part by acting as LXRβ agonists. This approach is linked to addressing the major genetic risk factor for AD, which is the apolipoprotein APOE4.
    1. Yu, L., Tasaki, S., Schneider, J. A., Arfanakis, K., Duong, D. M., Wingo, A. P., Wingo, T. S., Kearns, N., Thatcher, G. R. J., Seyfried, N. T., Levey, A. I., De Jager, P. L., and Bennett, D. A. (2020) Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons, JAMA Psychiatry.
    2. Knopp, R. C., Lee, S. H., Hollas, M., Nepomuceno, E., Gonzalez, D., Tam, K., Aamir, D., Wang, Y., Pierce, E., BenAissa, M., and Thatcher, G. R. J. (2020) Interaction of oxidative stress and neurotrauma in ALDH2(-/-) mice causes significant and persistent behavioral and pro-inflammatory effects in a tractable model of mild traumatic brain injury, Redox Biol 32, 101486.
    3. Gaisina, I. N., Lee, S. H., Kaidery, N. A., Ben Aissa, M., Ahuja, M., Smirnova, N. N., Wakade, S., Gaisin, A., Bourassa, M. W., Ratan, R. R., Nikulin, S. V., Poloznikov, A. A., Thomas, B., Thatcher, G. R. J., and Gazaryan, I. G. (2018) Activation of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors, ACS Chem Neurosci 9, 894-900.
    4. Tai, L. M., Koster, K. P., Luo, J., Lee, S. H., Wang, Y. T., Collins, N. C., Ben Aissa, M., Thatcher, G. R., and LaDu, M. J. (2014) Amyloid-beta pathology and APOE genotype modulate retinoid X receptor agonist activity in vivo, J Biol Chem 289, 30538-30555
  3. In addition to APOE4 risk, women are at greater risk of AD; the exact cause is unknown, but there are extensive studies on the link between menopause, leading to loss of circulating estrogens, and AD. Breast cancer therapy usually involves chemical or surgical menopause and epidemiology has looked at the risk of dementia, although insomnia is a confounding factor. Definitively, women who undergo early oophorectomy have a significantly increased risk of dementia in later life. In our collaborations with the late, great Judy Bolton, we explored estrogen replacement therapy (ERT) and selective estrogen receptor (ER) modulators (SERMs) extensively, both from the perspective of risk/benefit balance associated with ERT and the pursuit on an “ideal SERM” that might provide a safer alternative to ERT. Currently a brain-bioavailable selective human ER partial agonist (ShERPA) is being studied in familial AD transgenic (FAD-Tg) mice that express human apoE isoforms.
    1. Bolton, J. L., and Thatcher, G. R. J. (2008) Potential mechanisms of estrogen quinone carcinogenesis, Chem Res Toxicol 21, 93-101.
    2. Yu, B., Dietz, B. M., Dunlap, T., Kastrati, I., Lantvit, D. D., Overk, C. R., Yao, P., Qin, Z., Bolton, J. L., and Thatcher, G. R. J. (2007) Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms, Mol Cancer Ther 6, 2418-2428.  
    3. Qin, Z., Kastrati, I., Ashgodom, R. T., Lantvit, D. D., Overk, C. R., Choi, Y., van Breemen, R. B., Bolton, J. L., and Thatcher, G. R. J. (2009) Structural modulation of oxidative metabolism in design of improved benzothiophene selective estrogen receptor modulators, Drug Metab Dispos 37, 161-169.
    4. Hemachandra, L. P., Patel, H., Chandrasena, R. E., Choi, J., Piyankarage, S. C., Wang, S., Wang, Y., Thayer, E. N., Scism, R. A., Michalsen, B. T., Xiong, R., Siklos, M. I., Bolton, J. L., and Thatcher, G. R. J. (2014) SERMs attenuate estrogen-induced malignant transformation of human mammary epithelial cells by upregulating detoxification of oxidative metabolites, Cancer Prev Res (Phila) 7, 505-515.
    5. VandeVrede, L., Abdelhamid, R., Qin, Z., Choi, J., Piyankarage, S., Luo, J., Larson, J., Bennett, B. M., and Thatcher, G. R. (2013) An NO donor approach to neuroprotective and procognitive estrogen therapy overcomes loss of NO synthase function and potentially thrombotic risk, PLoS One 8, e70740.
  4. As part of the Bolton/Thatcher collaboration, we established significant literature in design, synthesis, mechanism, and metabolism of ER modulators, notably benzothiophene ligands related to raloxifene. This unique and holistic understanding is now permitting us to design novel ligands for estrogen receptors (ER), which are capable of tissue selective partial agonism, antagonism, and degradation (SERDs and PROTACs). We pursued these ligands as breast cancer therapeutics. Although ER+ breast cancer is well treated with endocrine therapy and increasing classes of targeted therapeutic agents, resistance to therapy occurs in more than half of patients, leading to metastatic disease: the majority of breast cancer victims have ER+ disease. Two distinct therapeutic approaches, have led to drugs from our labs completing clinical trials, a ShERPA and a selective ER degrader (SERD). A brain-SERD (BSERD) is poised for IND studies to treat breast cancer patients with brain metastases who have very poor prognosis and no targeted therapies.
    1. Lu, Y., Gutgesell, L. M., Xiong, R., Zhao, J., Li, Y., Rosales, C. I., Hollas, M., Shen, Z., Gordon-Blake, J., Dye, K., Wang, Y., Lee, S., Chen, H., He, D., Dubrovyskyii, O., Zhao, H., Huang, F., Lasek, A. W., Tonetti, D. A., and Thatcher, G. R. J. (2019) Design and Synthesis of Basic Selective Estrogen Receptor Degraders for Endocrine Therapy Resistant Breast Cancer, J Med Chem 62, 11301-11323.
    2. Molloy, M. E., White, B. E., Gherezghiher, T., Michalsen, B. T., Xiong, R., Patel, H., Zhao, H., Maximov, P. Y., Jordan, V. C., Thatcher, G. R.J., and Tonetti, D. A. (2014) Novel selective estrogen mimics for the treatment of tamoxifen-resistant breast cancer, Mol Cancer Ther 13, 2515-2526.
    3. Abderrahman, B., Maximov, P. Y., Curpan, R. F., Hanspal, J. S., Fan, P., Xiong, R., Tonetti, D. A., Thatcher, G. R. J., and Jordan, V. C. (2020) Pharmacology and Molecular Mechanisms of Clinically Relevant Estrogen Estetrol and Estrogen Mimic BMI-135 for the Treatment of Endocrine-Resistant Breast Cancer, Mol Pharmacol 98, 364-381.
  5. The development of SERDs, B-SERDs, and ShERPAs was driven by breast cancer cell lines resistant to endocrine therapy and resistant to the newer targeted therapeutics, fulvestrant and Cdk4/6 inhibitors (e.g. Palbociclib). All our work uses drug-resistant cell lines in order to find treatments for metastatic breast cancer. Since BET bromodomain proteins enhance the transcriptional effects of ER, BET inhibitors were developed to treat these resistant tumors. BET proteins are epigenetic readers binding to acetylated histones to stabilize transcriptional complexes at DNA. Our BET inhibitors have proven most impressive in combination with checkpoint inhibitors in pancreatic cancer and in non-cancer indications, such as fibrosis (both unpublished). Both the effects in pancreatic cancer and firbrosis derive from regulation of the immune response. Other immune-oncology projects are approaching the role of MLK3 and other kinases in T-cell activation and sensitization to checkpoint inhibitors; aiming for a dual kinase inhibitor for therapy of solid tumors.
    1. ​​​​​​​Li, Y., Zhao, J., Gutgesell, L. M., Shen, Z., Ratia, K., Dye, K., Dubrovskyi, O., Zhao, H., Huang, F., Tonetti, D. A., Thatcher, G. R. J., and Xiong, R. (2020) Novel Pyrrolopyridone Bromodomain and Extra-Terminal Motif (BET) Inhibitors Effective in Endocrine-Resistant ER+ Breast Cancer with Acquired Resistance to Fulvestrant and Palbociclib, J Med Chem 63, 7186-7210.
    2. Patel, H. K., Siklos, M. I., Abdelkarim, H., Mendonca, E. L., Vaidya, A., Petukhov, P. A., and Thatcher, G. R. (2014) A chimeric SERM-Histone deacetylase inhibitor approach to breast cancer therapy, ChemMedChem 9, 602-613.
    3. Kastrati, I., Siklos, M. I., Brovkovych, S. D., Thatcher, G. R. J., and Frasor, J. (2017) A Novel Strategy to Co-target Estrogen Receptor and Nuclear Factor kappaB Pathways with Hybrid Drugs for Breast Cancer Therapy, Horm Cancer 8, 135-142.
    4. Kastrati, I., Litosh, V. A., Zhao, S., Alvarez, M., Thatcher, G. R. J., and Frasor, J. (2015) A novel aspirin prodrug inhibits NFkappaB activity and breast cancer stem cell properties, BMC Cancer 15, 845.
    5. Kumar, S., Singh, S. K., Viswakarma, N., Sondarva, G., Nair, R. S., Sethupathi, P., Sinha, S. C., Emmadi, R., Hoskins, K., Danciu, O., Thatcher, G. R. J., Rana, B., and Rana, A. (2020) Mixed lineage kinase 3 inhibition induces T cell activation and cytotoxicity, Proc Natl Acad Sci U S A 117, 7961-7970.
    6. Kumar, S., Singh, S. K., Viswakarma, N., Sondarva, G., Nair, R. S., Sethupathi, P., Dorman, M., Sinha, S. C., Hoskins, K., Thatcher, G., Rana, B., and Rana, A. (2020) Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8(+) T cells, J Immunother Cancer 8.
  6. Estradiol and several SERMs undergo oxidative metabolism to generate quinones that may redox cycle and covalently modify biomolecules, which may contribute to the risk associated with ERT. Chemical carcinogenesis caused by exposure to estrogen oxidative metabolites from menarch to menopause is believed to be linked to breast cancer. The SERM tamoxifen undergoes Phase 1 and Phase 2 metabolism to yield an electrophile that reacts with DNA and may be the cause of uterine cancer risk associated with tamoxifen. Consequently, we have had a strong interest in protein covalent modification and its potential in enzyme inhibition and also to induce toxicity.
    1. ​​​​​​​Peng, K. W., Wang, H., Qin, Z., Wijewickrama, G. T., Lu, M., Wang, Z., Bolton, J. L., and Thatcher, G. R. (2009) Selective estrogen receptor modulator delivery of quinone warheads to DNA triggering apoptosis in breast cancer cells, ACS Chem Biol 4, 1039-1049.
    2. Wang, Z., Wijewickrama, G. T., Peng, K. W., Dietz, B. M., Yuan, L., van Breemen, R. B., Bolton, J. L., and Thatcher, G. R. J. (2009) Estrogen Receptor {alpha} Enhances the Rate of Oxidative DNA Damage by Targeting an Equine Estrogen Catechol Metabolite to the Nucleus, J Biol Chem 284, 8633-8642.
    3. Pierce, E. N., Piyankarage, S. C., Dunlap, T., Litosh, V., Siklos, M. I., Wang, Y. T., and Thatcher, G. R. J. (2016) Prodrugs Bioactivated to Quinones Target NF-kappaB and Multiple Protein Networks: Identification of the Quinonome, Chem Res Toxicol 29, 1151-1159.
    4. Kastrati, I., Siklos, M. I., Calderon-Gierszal, E. L., El-Shennawy, L., Georgieva, G., Thayer, E. N., Thatcher, G. R., and Frasor, J. (2016) Dimethyl Fumarate Inhibits the Nuclear Factor kappaB Pathway in Breast Cancer Cells by Covalent Modification of p65 Protein, J Biol Chem 291, 3639-3647.
    5. Liu, J., Li, Q., Yang, X., van Breemen, R. B., Bolton, J. L., and Thatcher, G. R. J. (2005) Analysis of protein covalent modification by xenobiotics using a covert oxidatively activated tag: raloxifene proof-of-principle study, Chem Res Toxicol 18, 1485-1496.
    6. Silvestri, I., Lyu, H., Fata, F., Banta, P. R., Mattei, B., Ippoliti, R., Bellelli, A., Pitari, G., Ardini, M., Petukhova, V., Thatcher, G. R. J., Petukhov, P. A., Williams, D. L., and Angelucci, F. (2020) Ectopic suicide inhibition of thioredoxin glutathione reductase, Free Radic Biol Med 147, 200-211.
  7. Our early research made significant contributions in the physical organic and biological chemistry of phosphorylation reactions, a reaction central to post-translational modification (PTM). The application of this expertise to reactions underpinning chemical biology has been used in studying PTMs and covalent modification by NO, H2S, RSNO, and xenobiotics and their metabolites.  Work on NO and “nitrosylation” has challenged dogma. We have developed new chemoproteomics approaches to study cysteome PTMs to enable these studies. In addition, our expertise in protein covalent modification provides knowledge of mechanism of action required to design safer drugs.
    1. ​​​​​​​Sinha, V., Wijewickrama, G. T., Chandrasena, R. E., Xu, H., Edirisinghe, P. D., Schiefer, I. T., and Thatcher, G. R. J. (2010) Proteomic and mass spectroscopic quantitation of protein S-nitrosation differentiates NO-donors, ACS Chem Biol 5, 667-680.
    2. Wang, Y. T., Piyankarage, S. C., Williams, D. L., and Thatcher, G. R. J. (2014) Proteomic profiling of nitrosative stress: protein s-oxidation accompanies s-nitrosylation, ACS Chem Biol 9, 821-830.
    3. Wang, Y.-T., Piyankarage, S. C., and Thatcher, G. R. J. (2016) Quantitative Profiling of Reversible Cysteome Modification Under Nitrosative Stress, in Neuromethods, pp 1-18, Humana Press, Totowa, NJ.
    4. Yao, Y., Delgado-Rivera, L., Samareh Afsari, H., Yin, L., Thatcher, G. R. J., Moore, T. W., and Miller, L. W. (2018) Time-Gated Luminescence Detection of Enzymatically Produced Hydrogen Sulfide: Design, Synthesis, and Application of a Lanthanide-Based Probe, Inorg Chem 57, 681-688.
    5. Yao, Y., Kong, C., Yin, L., Jain, A. D., Ratia, K., Thatcher, G. R., Moore, T. W., Driver, T. G., and Miller, L. W. (2017) Time-Gated Detection of Cystathionine gamma-Lyase Activity and Inhibition with a Selective, Luminogenic Hydrogen Sulfide Sensor, Chemistry 23, 752-756.
  8. Our published contributions to anti-infective drug discovery derive from two long-term collaborations with lijun Rong on inhibition of viral entry and with David Williams on Schistosomiasis, disease caused by infection with freshwater parasitic worms in tropical and subtropical countries. Inhibition of viral entry can be effective in vitro and in mouse models, but as we have been learning with SARS-CoV-2: 1) drugs such as remdesivir that seem effective in vitro have very little clinical efficacy; and, 2) the individual response to infection varies widely and is not simply related to viral load. In March, we initiated a project to discover small molecules that inhibit the interaction of CoV-2 viral proteases with human target proteins that disrupt the immune system.
    1. ​​​​​​​Cooper, L., Schafer, A., Li, Y., Cheng, H., Medegan Fagla, B., Shen, Z., Nowar, R., Dye, K., Anantpadma, M., Davey, R. A., Thatcher, G. R., Rong, L., and Xiong, R. (2020) Screening and Reverse-Engineering of Estrogen Receptor Ligands as Potent Pan-Filovirus Inhibitors, J Med Chem.
    2. Gaisina, I. N., Peet, N. P., Wong, L., Schafer, A. M., Cheng, H., Anantpadma, M., Davey, R. A., Thatcher, G. R. J., and Rong, L. (2020) Discovery and Structural Optimization of 4-(Aminomethyl)benzamides as Potent Entry Inhibitors of Ebola and Marburg Virus Infections, J Med Chem 63, 7211-7225.
    3. Gaisina, I. N., Peet, N. P., Cheng, H., Li, P., Du, R., Cui, Q., Furlong, K., Manicassamy, B., Caffrey, M., Thatcher, G. R. J., and Rong, L. (2020) Optimization of 4-Aminopiperidines as Inhibitors of Influenza A Viral Entry That Are Synergistic with Oseltamivir, J Med Chem 63, 3120-3130.
    4. Lyu, H., Petukhov, P. A., Banta, P. R., Jadhav, A., Lea, W. A., Cheng, Q., Arner, E. S. J., Simeonov, A., Thatcher, G. R. J., Angelucci, F., and Williams, D. L. (2020) Characterization of Lead Compounds Targeting the Selenoprotein Thioredoxin Glutathione Reductase for Treatment of Schistosomiasis, ACS Infect Dis 6, 393-405.
    5. Silvestri, I., Lyu, H., Fata, F., Boumis, G., Miele, A. E., Ardini, M., Ippoliti, R., Bellelli, A., Jadhav, A., Lea, W. A., Simeonov, A., Cheng, Q., Arner, E. S. J., Thatcher, G. R. J., Petukhov, P. A., Williams, D. L., and Angelucci, F. (2018) Fragment-Based Discovery of a Regulatory Site in Thioredoxin Glutathione Reductase Acting as "Doorstop" for NADPH Entry, ACS Chem Biol 13, 2190-2202.
    6. Ziniel, P. D., Karumudi, B., Barnard, A. H., Fisher, E. M., Thatcher, G. R. J., Podust, L. M., and Williams, D. L. (2015) The Schistosoma mansoni Cytochrome P450 (CYP3050A1) Is Essential for Worm Survival and Egg Development, PLoS Negl Trop Dis 9, e0004279.

 

 


Todd Vanderah, PhD
Department Head, Pharmacology
Professor, Anesthesiology
Professor, Neurology
Professor, Neuroscience
Professor, Pharmacology
Professor, Physiological Sciences

Todd Vanderah has worked in the area of Neuropharmacology for over 20 years, resulting in 165 peer-reviewed publications and continuous funding from the National Institute of Health. His work focuses on identifying novel molecular targets on pain pathways in order to attenuate acute and chronic pain while reducing unwanted side effects. Recently he has investigated the use of an Angiotensin fragment that inhibit chronic inflammation while inhibiting inflammation-induced cognitive impairment.

Dr. Vanderah’s previous experience with drug development stems from his 4.5 years of work at Ferring Pharmaceuticals Inc., where he was responsible for drug development, including efficacy, side effects and pharmacokinetics. He also developed three compounds from the preclinical side that were pushed into clinical phase testing. One of the three has made it onto the market, the second is on the market in Europe and the third has been sold to another company, but is still in development.


Wei Wang, PhD
Co-Director, Arizona Center for Drug Discovery
Professor, Pharmacology and Toxicology

Wei Wang is a new addition to the College of Pharmacy team, responsible for advancing the mission of drug discovery at both the University of Arizona Health Sciences Center and main campus. By uniting the university’s state-of-the-art facilities, expertise and resources, he will help facilitate drug discovery and development while enhancing translational research collaboration.

Dr. Wang is in the top 5% of authors cited in the field of chemistry with H-index of 70. His research interests include organic synthesis, molecular imaging and recognition, chemical biology and medicinal chemistry (drug discovery). He is an author or co-author of more than 240 original research papers and 17 books/book chapters. He has six scientific patents and is a peer-reviewer for more than 60 national and international journals.


Celina Zerbinatti, PhD
Associate Professor
Co-Director, Arizona Center for Drug Discovery

Celina Zerbinatti, PhD, is Co-Director of the Arizona Center for Drug Discovery (ACDD) and Associate Professor in the Department of Pharmacology and Toxicology at the University of Arizona College of Pharmacy, Tucson. Dr. Zerbinatti obtained her BS, MS and PhD degrees from the University of São Paulo, Brazil, and completed her postdoctoral training at Washington University School of Medicine in St Louis, MO. Dr. Zerbinatti is an accomplished senior leader from the pharmaceutical sector. She gained extensive drug discovery experience at Merck Research Laboratories, where she led program teams in the area of neuroscience for almost 10 years. She then joined Evotec AG as the scientific and operational head of a broad drug discovery alliance on Huntington's disease with the CHDI Foundation. Expanding into the biotech sector, Dr. Zerbinatti was a senior consultant for the Dementia Discovery Fund at SV Health Investors and, most recently, the head of biology at E-Scape Bio, a clinical stage biotechnology company focused on the discovery and development of small molecule drugs to treat genetically-defined neurodegenerative diseases. Dr. Zerbinatti is currently a scientific advisor for Reglagene, a spin-off company from the University of Arizona developing novel medicines to control gene expression through targeting of DNA quadruplexes. She is also a senior consultant for drug discovery at the Lieber Institute for Brain Development, a privately-funded institute affiliated with John Hopkins University focused on Schizophrenia research.

 

Areas of Interest:

Drug Discovery 
Target Validation
Assay Development 
High Throughput Screening
In Vitro Pharmacology
In Vivo Pharmacology
Disease Model Development
Biomarker Discovery