ACDD Core Team

Andrew Capaldi
Associate Professor, Molecular and Cellular Biology
Associate Professor, Genetics - GIDP
Associate Professor, BIO5 Institute

Christopher Hulme, PhD
Professor, Pharmacology and Toxicology
Director, Medicinal Chemistry
BIO5 Drug Discovery

Dr. Christopher Hulme is director of medicinal chemistry at the BIO5 Translational Drug Discovery Center and is focused on small molecule drug design and developing enabling chemical methodologies to expedite the drug discovery process. The development of small molecule inhibitors of kinases is of particular interest. Projects are highly collaborative in nature, and students are exposed to the full array of design hurdles involved in progressing molecules along the value chain to clinical evaluation.

1. Therapies for Alzheimer’s and Neurodegenerative Diseases
With 24.3 million people affected in 2005 and an estimated rise to 45 million in 2020, dementia is currently a leading unmet medical need and a costly burden on public health. Seventy percent of these cases have been attributed to Alzheimer’s disease (AD), a neurodegenerative pathology whose most evident symptom is a progressive decline in cognitive functions. Studies in the group focus on providing a significant mechanistic alternative to common approaches that solely focus on small molecule design toward APP-cleavage inhibition. In particular, ongoing efforts are aimed at the design of structurally novel small molecule inhibitors of the dual-specificity tyrosine phosphorylation–regulated kinase 1A (DYRK1A) and their evaluation of in vivo activity and measurement of in vivo tau phosphorylation and neurofibrillary tangles pathology in 3X-TgAD mouse models of AD. Moreover, DYRK1A has also been suggested to affect other cellular pathways that may be involved in mental impairment and neurodegenerative dementia.

Studies are being conducted with a long-term collaborator (Dr. Travis Dunckley) at Translational Genomics (TGen). Inhibition of DYRK1A functioning should theoretically mitigate multiple processes underlying the progression of neurodegeneration, particularly in the AD-related therapeutic area, for which key DYRK1A substrates include: (1) tau protein, (2) amyloid precursor protein, and (3) presenilin 1 (the catalytic subunit of γ-secretase), all pointing to clear mechanisms through which elevated DYRK1A activity may be promoting AD progression. Several other AD-related kinases are targets of current interest in the group (Smith B, Medda F, Gokhale V, Dunckley T, Hulme C [2012] Recent Advances in the Design, Synthesis, and Biological Evaluation of Selective DYRK1A Inhibitors: A New Avenue for a Disease Modifying Treatment of Alzheimer’s. ACS Chem. Neurosci., DOI: 10.1021/cn300094k).

2. Therapeutics Modulating Prostaglandin E2Production
Prostaglandin E2 (PGE2) is well known to play a pivotal role in processes associated with inflammation, pain, and pyresis and is over-expressed in various tumors where chronic inflammation has been linked to the growth of various cancerous tissues. Indeed, PGE2 has been identified as the major prostaglandin associated with the progression of various tumor malignancies, including that of the colon, lung, and breast. An ongoing project within the group is the development of novel small molecules that mitigate PGE2 production and display antitumor growth properties in vivo. Several novel series of small molecules have been developed and are under further investigation (Smith B, Chang HH, Medda F, Gokhale V, Dietrich J, Davis A, Meuillet EJ, Hulme C [2012] Synthesis and biological activity of 2-aminothiazoles as novel inhibitors of PGE2 production in cells. Bioorg. Med. Chem. Lett., 22:3567–3570).

3. Enabling Chemical Methodologies
a. Applications of Multi-Component Reactions

The group also has a long-standing interest in the development of new reactions that produce biologically relevant molecules in an efficient manner. Indeed, front-loading screening collections with molecules possessing high “iterative efficiency potential” is critical for expediting the drug discovery process. Compounds derived from multi-component reactions (MCRs) demonstrate such potential, and thus their discovery and applications are of utmost importance. Closely linked with the Molecular Libraries Small Molecule Repository, the group seeks to develop an operationally friendly chemistry that delivers products of high molecular diversity that ultimately enable library production and deposition of compounds in both national and local screening collections. A one-pot five-step transformation developed in the group is depicted (Xu Z, De Moliner F, Cappelli A, Hulme C [2012] Ugi/Aldol Sequence: Expeditious Entry to Several Families of Densely Substituted Nitrogen Heterocycles. Angewandte Chem., Int. Ed., 51:8037–8040).

Recent discoveries in the group have facilitated a new project toward the expeditious syntheses and application of novel dendrimer families, repetitively branched molecules that show high promise in drug delivery, gene delivery, and sensor technologies.

b. New Hypervalent Iodine Methodology and Applications
Novel hypervalent iodine–mediated C-H activation methodologies and their application for the preparation of novel peptidomimetics are an active area of research.

c. Organoselenium Chemistry
A recent discovery of a new selenium dioxide–mediated oxidative amidation is driving new studies in molecular diversity generation.

View UA Profile


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

Hongmin Li, PhD, joined the College of Pharmacy, University of Arizona Tucson in 2020 from the Wadsworth Center, New York State Department of Health. During the last 20 years, my laboratory focuses on both basic and translational sciences. In basic science part, we investigate the structures, functions and mechanisms of essential macromolecules involved in various cellular actions and disease processes. The knowledge gained from these basic science studies leads to the second category, the drug discovery part where we develop novel biochemical and cellular assays for different drug targets, carry out high throughput screening (HTS) assays to identify novel target-based inhibitors, perform cellular antiviral/antifungal/anti-cancer assays, and conduct ADMET profiling and mouse model efficacy studies for lead compounds.

My laboratory has developed a research platform that integrates virology, mycology, bacteriology, RNA, biochemistry, structural biology, cellular biology, and in vivo animal model in the same lab. We also work closely with collaborators and colleagues in the aspects of medicinal chemistry, computational biology, immunology, cancer biology, and in vivo pharmacokinetics and pharmacodynamics (PK/PD).

The Li laboratory has been continuously funded by the NIH and various foundations since 2002. Currently, the main research focuses on development of therapeutics against cancers and human pathogens such as dengue virus, Zika virus, SARS-CoV-2, Cryptococcal fungi and Mycobacterium tuberculosis. Students and postdoctors joining in the lab will have opportunities to explore all areas in the Li laboratory, as stated above. We currently have multiple positions opening at all levels (undergraduate and graduate students, technician, and postdoc).  Please visit talent.arizona.edu to apply for open positions.

Research projects:

  1. Orthosteric and allosteric inhibition of flavivirus NS2B/NS3 protease complex. Viral protease is an attractive target for therapeutic intervention. The HIV and HCV proteases are good examples as antiviral targets. The flavivirus protease, a two-component complex consisting of viral proteins NS3 and NS2B (cofactor), is responsible for cleavage of the polyprotein precursor (PP) produced by the viral genome. Most attempts to develop flavivirus protease inhibitors have focused on the NS3 active site with very limited success. We have successfully developed high throughput screening (HTS) assays. Our pilot HTS was very successful, identifying several existing drugs as potent flavivirus protease inhibitors, with both in vitro and in vivo activities. The project is currently on-going to screen larger NIH libraries to identify novel inhibitors with new scaffolds. We are collaborating with medicinal chemists, experts in drug metabolism, computational biologists, and virologists to develop potent protease inhibitors with various mechanisms.
  2. Nanobodies as therapeutics for flavivirus management. All flaviviruses are coated with their own envelope (E) protein. Neutralizing antibodies against the E protein have been identified. However, due to antibody-dependent enhancement (ADE), these antibodies are not ideal candidates as therapeutics. In contrast, a single domain, termed VHH (variable domain of camelid heavy-chain-only antibody (HcAb)) or nanobody (Nb) has emerged as an effective drug candidate for various applications, including infectious disease management. Compared to conventional antibodies, Nbs do not have the Fc domain that is required for enhanced disease, thus eliminating ADE. In this project, we will screen Nb-containgin phage libraries, perform viral plaque reduction neutralization test, viral entry inhibition, ADE evaluation, viral resistance, affinity measurement, epitope mapping, co-crystal structure, Cryo-EM, and mutagenesis studies. We will generate both virus specific and broad-spectrum neutralizing Nbs for flavivirus management. We will follow up with in vivo pharmacokinetics and antiviral efficacy using animal disease models.
  3. Inteins as drug targets for intein-containing mycobacteria and fungi. Inteins are internal self-splicing protein elements that self-excise from their host proteins and catalyze ligation of the flanking sequences (exteins) with a natural peptide bond. Many human pathogens contain inteins in their genes. For example, Mycobacterium tuberculosis (Mtu) harbors inteins in three genes: RecA recombinase, DnaB helicase, and SufB iron-cluster assembly gene. All three functions are required for virulence, with DnaB and SufB being essential for bacterial growth. The fungi, Cryptococcus neoformans (Cne), C. gattii (Cga), and Aspergillus fumigatus (Afu), contain inteins in their Prp8 genes (Prp8: pre-mRNA processing 8, an essential component of spliceosome). It is worth noting that inteins only exist in certain microbes, mammals including human beings do not have intein elements in their genes. Based on these analyses, we hypothesize that inteins are attractive drug targets for management of intein-containing microbial infections. We have determined the crystal structures of the Prp8 intein, various forms of the RecA intein, and a class III DnaB intein. We showed that cisplatin, an FDA-approved chemotherapeutics, not only inhibits the intein splicing in vitro, but also significantly reduces the fungal burden in lungs using an in vivo cryptococcosis mouse model. Using genetic approaches, we have also generated an intein-free cryptococcal strain to characterize inhibitor specificity. Moreover, we have developed HTS assays to help screen intein splicing inhibitors. The project will proceed to HT screens.
  4. Mechanism, function and inhibition of the Hectd3 E3 ubiquitin ligase. Protein ubiquitination is sequentially mediated by three enzymes: the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3) that controls substrate specificity. Recently we studied a HECT-containing E3 ligase, Hectd3, which has recently become a hot topic. Hectd3 is a much understudied E3 ligase with only a dozen publications to date. Hectd3 is considered an injurious gene that promotes cancer cell survival, enables pathogenesis of multiple sclerosis (MS), and facilitates infections of microbial pathogens such as intracellular bacteria Francisella novicida, Mycobacteria, and Listeria. Importantly, as a host factor, Hectd3 is dispensable for the host as Hectd3–/– mice were viable and normal. At mechanistic level, we and others found that Hectd3 interacts with and/or ubiquitinates multiple substrates (caspase-8, caspase-9, Malt1, TRAF3, HSP90, CRAF, and Stat3), leading to non-degradative polyubiquitination of target proteins, stabilizing them, and thus inducing drug resistance in cancer cells or promoting Th17 pathogenic T-cells differentiation in experimental autoimmune encephalomyelitis (EAE), a mouse model for human multiple sclerosis. For this project, we aim to investigate the mechanism, function, and inhibition of Hectd3. We will determine its complexes with substrate and the E2 conjugating enzyme using X-ray and Cryo-EM. We will also develop HTS assays to identify inhibitors. These basic and translational sciences will greatly advance our understanding of this novel E3 ligase and facilitate development of novel therapies for disease management.

Tim Marlowe, PhD
Arizona Center for Drug Discovery Core Team Member
Director, Molecular Discovery Core
Assistant Professor, Internal Medicine, COM - P

Jon T. Njardarson, PhD
Professor, Chemistry and Biochemistry

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.

 

 


Curtis Thorne, PhD
Arizona Center for Drug Discovery Core Team Member
Assistant Professor, Cellular and Molecular Medicine
Assistant Professor, BIO5 Institute
Member, University of Arizona Cancer Center
Member, Steele Children's Research Center

Research Summary: Discovery and characterization of GSK-3 activators as anti-cancer compounds

Small molecule inhibition of kinase activity is well established as a fruitful therapeutic strategy in oncology. Yet, almost completely neglected is the development of small molecule kinase activators for rationally selected targets. The protein kinase GSK-3 is an outstanding candidate for small molecule activation due to its many allosteric pockets, its central role in tumorogenesis, and its inactivation in numerous cancers. Our work suggests that intestinal cancers may be exquisitely sensitive to GSK-3 activators and that activating GSK-3 would sensitize cancer cells to other therapies. Our research plan is to discover first-in-class GSK-3 activators by screening compound libraries with a biochemical kinase assay followed by complex organoid-based secondary screen. Utilizing a new high-dimensional structure-activity relationship (HD-SAR) approach we have developed, we will categorize the lead compounds into regulators of 3 major processes; 1) proliferation, 2) metabolism, and 3) cytoskeleton. From this drug discovery project, we will characterize small molecules that selectively target and activate GSK-3, useful for testing its function in various physiological and pathophysiological settings. To our knowledge, this proposal represents the first to directly attempt the discovery of “kinase activators”, thus it is high-risk with a potential high-reward. With successful proof-of-principle, we envision kinase activators targeting many of the ~500 known protein kinases becoming a major therapeutic strategy pursued academically and industry-wide. We propose to discover a new class of anti-cancer therapeutic, GSK-3 activators, and demonstrate their efficacy toward intestinal cancers (second deadliest cancer in the western world), thereby establishing an immediate and significant therapeutic utility for lead compounds arising from this project.

Thorne Lab: http://thornelab.org/


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 Research Professor, Pharmacology and Toxicology
Co-Director, Arizona Center for Drug Discovery

Celina Zerbinatti, PhD, is Co-Director of the Arizona Center for Drug Discovery (ACDD) and Associate Research 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 senior consultant for the Dementia Discovery Fund at SV Health Investors and Head of Biology at Escape Bio, a clinical stage biotechnology company focused on the discovery and development of small molecule drugs to treat genetically-defined neurodegenerative disorders. Dr. Zerbinatti is currently a consultant for the Lieber Institute for Brain Development, a privately-funded institute affiliated with John Hopkins University focused on Schizophrenia research, and for Kisbee Therapeutics, a startup founded by Stuart Schreiber (Broad Institute), Ben Cravatt (Scripps) and Jennifer Lippincott-Schwartz (HHMI Janelia) that is focused on the development of apolipoprotein E-based therapies for neurological disorders.

 

Areas of Interest:

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