The Prebys Center conducts drug discovery research in diverse disease areas such as autoimmunity, cardiovascular and metabolic diseases, cancer and neurodegenerative disorders.
Our drug discovery experts and capabilities enable world-class research. Our capabilities are described below, and are followed by some current and past examples of our research productivity.
Drug discovery technology
Our Assay Development team has deep expertise in innovative biochemical and biophysical approaches. We use biologically-relevant and agnostic approaches, developing the best assay for each specific target. In addition to know-how, the team is supported by cutting edge technology, such as the label-free EPIC.
The Cell Biology group is focused on development of patient cell specific and human induced pluripotent stem cell (hiPSC)-based disease models for drug screening and target identification. They aim to design human cell based assays that reflect higher order cellular functions and recapitulate disease phenotypes, yet have the throughput and reproducibility required for drug discovery.
The Cheminformatics group is led by Dr. Sumeet Salaniwal, who has over 15 years of experience in computational drug discovery. The Cheminformatics group leads the design, development, implementation and support of complex scientific information and data systems in support of the Prebys Center’s drug discovery pipeline. The group applies fundamentals of cheminformatics, quantitative SAR modeling, molecular modeling, computer-aided drug design, advanced structure searching, and library design and diversity analysis towards to identification, design and optimization of drug candidates. Cheminformatics also designs and implements computational algorithms to enable intelligent drug discovery automation.
High Content Imaging Platforms
The High Content Imaging (HCI) Platforms group performs assay development, screening, and data analysis/mining for high content screens, where the readout is based on images obtained using high-throughput microscopy systems. In fact, the Prebys Center has developed over 50 HCS assays, many using immunofluorescence markers against endogenous proteins, in 384- and 1,536-well formats. More than 20 of these assays have been successfully converted to large-scale HC screens and demonstrate robustness typically required for both Hit Identification as well as SAR support. The HCI Platforms scientists provide expertise in all areas of high content image-based screens including microscopy instrumentation, assay biology and assay design/proof-of-concept, sample preparation, image acquisition, image analysis, image data management, data mining, and algorithm development. Developed assays range from detection of β-arrestin-GFP GPCR activity, to cell shape and cytoskeletal rearrangement and complex multiplexed, multi-parametric kidney podocyte or cell health profiling assays, and include advanced methods such as FRET imaging, 3D spheroid analyses, and cell migration assays.
The HCI Platforms team is also responsible for implementation, maintenance, and enhancements of the complex HCI platform infrastructure and workflows, which enable routine screening of small (<1,000) to large-scale (>100,000) chemical compound libraries using image-based phenotypic assays. The HCI infrastructure includes several confocal and/or widefield imaging systems from 4x to 60x magnifications with high resolution objectives of up to 1.2 numerical aperture. Our HCI team has created numerous complex assay algorithms for rapid batch processing during large-scale HCS while also providing easy-to-use access to standard image analysis tools and workflows. They have also designed and implemented integrated automated microscopy systems with advanced photonics and robotics capabilities for automated use in both fixed and live-cell formats, including a robotic system enabling high-throughput multi-day time-lapse imaging experiments.
High Throughput Screening
High Throughput Screening (HTS) capabilities are fundamental to the drug discovery efforts of the Prebys Center. The facilities and expertise of the HTS team has enabled us, together with collaborators, to initiate translational research and discover the starting points for novel small molecule drug discovery. The group has developed highly advanced automation infrastructure including state-of-the-art liquid handling devices, multiple robotic integration systems as well as a diverse range of signal detection instruments. These activities are complimented and aided by the Compound Management team who deploy several automated sample management and liquid-handling instruments. Taken together this enables scientists to screen an array of diverse and large compound libraries.
In vitro Pharmacology (aka Bioanalytical/DMPK)
The in vitro ADME group is led by Michael Gardner. His 30 years of experience range from enzymology, protein purification, and radio-synthetic chemistry, to in vitro and in vivo pharmacology, which provides him with a broad and unique perspective. Lab support staff consists of one full time Ph.D. Pharmaceutical Scientist and one part-time Chemist.
The in vitro Pharmacology group at Sanford Burnham Prebys excels at quickly providing high quality results to the medicinal chemistry group in their drug development efforts. Having direct and immediate access to our scientific expertise is what sets us apart from contract research organizations and other service providers. In addition, we provide a core bioanalytical service to researchers within the Institute community that is competitive with outside vendors.
- Sciex API4000
The lab is equipped with a Sciex API4000 quadrupole mass spectrometer with linear ion trap (Qtrap) coupled to a Shimadzu Prominence liquid chromatograph with a six plate autosampler facilitating the bioanalytical analysis of small molecule compounds (MW<1500) in a variety of biological matrices in support of in vitro and in vivo experiments. It is also equipped with automated liquid handling instruments for high-throughput assays to determine aqueous solubility, permeability, metabolic stability, plasma stability, protein binding, cytotoxicity, and other in vitro ADME assays.
In Vivo Pharmacology
The Prebys Center In Vivo Pharmacology team uses a combination of pharmacokinetics, pharmacodynamics and efficacy studies to test therapeutic hypotheses and improve the drug-like properties of molecules, which are identified by the Prebys Center high-throughput screening teams and optimized by center chemists. We drive drug discovery by using state of the art technologies to interrogate complex disease pathophysiology and evaluate the therapeutic potential of novel drugs in diverse disease areas. Our scientists are well versed in whole organism physiology and excel at developing and examining disease models for most organ systems.
The Medicinal Chemistry team has extensive knowledge and experience in all aspects of drug discovery, including hit selection, initial SAR exploration and lead optimization. They have full analytical capabilities (LC-MS and NMR), and can re-purify, re-synthesize and scale up (to 50-100g) lead compounds. The team spearheads candidate compound selection and optimization and is integrated with the DMPK group, which performs in vitro ADME assays, including plasma and microsomal stability, protein binding, solubility and permeability, as well as in vivo PK.
Protein Production and Analysis
Custom recombinant protein production
The Protein Production and Analysis group generates custom protein constructs and expresses and purifies recombinant proteins for variety of drug discovery projects including cell-based and protein-based chemical library screening, assay development, hit conformation, characterization of drug candidate – target interaction, etc. Production is carried out in bacterial (E. coli),insect/baculovirus and mammalian expression systems, and involves cloning of target genes; generation cell lines/viruses; optimization of protein expression; development of protein purification protocols; and protein purification from large scale cell culture.
Biophysical protein analysis
Protein targets are characterized by variety of biophysical methods including analytical ultracentrifugation (AUC), differential scanning calorimetry (DSC), isothermal titration calorimetry(ITC), microscale thermophoresis (MST) and fast kinetics/stopped-flow. Data obtained from biophysical analysis are used for quality control of protein preparations, to assist design and troubleshooting of HTS assays, to confirm binding of HTS hits, and to guide structural biology(crystallization, NMR) drug discovery effort.
Project Management Capabilities
The Prebys Center has a team of dedicated, trained project managers who are experienced in small molecule drug discovery. We work with our internal and external project team members and collaborators to ensure clarity on objectives, critical path activities and interdependencies of a project plan. The team also provides resource management to ensure delivery of projects on time and on budget. We understand the importance of project governance and facilitate these processes both internally and externally with our partners to ensure open communication and expectations in decision making. Using the web-based industry leading project management tool “Workfront,” we keep track of project schedules, deliverables and group workload.
Structure-Guided Drug Design
Our Structure-Guided Drug Discovery group is led by Dr. Tarmo Roosild, who has expertise in the elucidation and analysis of protein structure. The group utilizes high-resolution structural biochemistry techniques and computational chemistry methods to expedite the translation of chemicals identified in screening experiments into highly efficacious and selective molecules, which can be advanced as candidate therapeutics for the treatment of human disease. The team routinely co-crystallizes target proteins in complex with bound small molecules and determines their atomic-resolution structures through X-ray diffractometry. For in-house diffraction data collection and analysis, we utilize a Rigaku FR-E SuperBright Ultra high-intensity rotating anode generator supplying two independent diffraction stations equipped with X-stream cryogenic systems and either a R-Axis HTC three-image plate detector or an R-Axis IV two-image plate detector. The Center also has access to SSRL’s macromolecular crystallography beamlines to enable acquisition of very high-quality data and prosecution of challenging targets which produce poorly diffracting crystals.
Select drug discovery grants
Neurological disorders and neurodegeneration grant awards
|Grant #||1 R21 DA038019 4 R33 DA038019|
|Title||Lead optimization of brain penetrant Neurotensin Receptor 1 agonists|
|Institute||SBP (Internal Grant)|
|Prebys Lead||Pinkerton, A|
|Description||There remains a major unmet medical need for an effective treatment for substance abuse disorders. The neurotensin system represents a promising target for the treatment of addiction, but its therapeutic utility has not been fully realized due to the ack of brain penetrant and systemically available compounds. To address this impediment, we will develop tool compounds to test the hypothesis that small molecule agonists of the neurotensin receptor 1 will reduce drug-seeking behaviors.|
|Title||National Cooperative Reprogrammed Cell Research Groups (NCRCRG) to Study Mental Illness (U19); iPSC-based platform development for major psychiatric disorder modeling and discovery|
|Prebys Lead||Bang, Anne|
|Description||The overarching goal of this NCRCRG is to develop a robust, scalable and generalizable platform to investigate the pathophysiology of psychiatric disease using induced pluripotent stem cells (iPSCs). The recent discovery that adult human somatic cells can be reprogrammed to a pluripotent state raises the exciting possibility that human neurons can be generated with the same genetic profile as patients, and disease mechanisms can now be investigated in relevant cell types. Because this new field is rapidly expanding and evolving, this is a critical time to bring together academic and industrial partners committed to standardizing the process of iPSC generation, cell type-specific differentiation, phenotypic assay development, and preparation for eventual high-throughput diagnostic and drug discovery. Formal partnerships and open communication between commercial entities and academic institutions will greatly facilitate this effort by ensuring that every stage of the proces is validated and amenable to industrial process control and standardization.
The function of Scientific Core C is to develop robust and reliable assays in miniaturized and higher throughput formats to support the three Research Projects. We will utilize expertise and instrumentation, including high content imaging, rapid kinetic analyses, and higher throughput electrophysiology available at the Prebys Center, a state of the art drug screening facility, which also houses a stem cell lab dedicated to establishing the technology platforms and reproducibility necessary to utilize iPSC derived cell types for phenotypic screening and drug testing. The proposed development of procedures to interrogate iPSC derived neural cell types in microtiter-well formats will be advantageous for both phenotype validation and discovery, as relatively small numbers of cells and reagents are required, making feasible testing of larger numbers of replicate samples and more variables, including timing and dose response to therapeutic agents, signaling pathway modulators, and stress inducers. In the long term, development of these assays will provide a foundation for future efforts aimed at target identification and drug discovery. Importantly, these assays will also form the bases of a standardized bank of tests against which broader panels of BP and SZ patient iPSCs, and iPSC from patients with other neuropsychiatric diseases can be screened.
|Grant #||CCMD 2015|
|FOA #||Cure CMD Midrange Grant|
|Title||High throughput screens to identify small molecules that ameliorate laminopathy phenotypes in patient cells|
|Prebys Lead||Bang, Anne|
|Grant #||1 R01 MH109655|
|Title||Optimization of glucocorticoid receptor (GR) passive antagonists for the treatment of post-traumatic stress disorder (PTSD)|
|Prebys Lead||Pinkerton, A|
|Description||Post-traumatic stress disorder (PTSD) is the 4th most common psychiatric disorder, and affects approximately 6.8% of the US population, and is associated with disturbed sleep, substance-related disorders, and increased mortality. Sertraline and paroxetine (serotonin reuptake inhibitors) are the most widely prescribed drugs; however their response is limited, particularly in combat veterans, and sleep disruption is unaffected by these agents. As there are no currently available pharmacological agents, which can be administered prior to or immediately following trauma, to effectively prevent the development of PTSD symptoms, we propose to further develop a series of highly unique compounds, which show great promise in the treatment of PTSD.|
Oncology grant awards
|Grant #||1 R01 CA193382|
|Title||HTS for Identification of Novel Inhibitors of Pyk2 Activity|
|Prebys Lead||Sergienko, E|
|Description||Malignant gliomas are a leading cause of CNS tumor-related death and survival statistics for patients with malignant glioma have not shown any significant improvement during the past 20 years underscoring the importance for new insights into therapeutic targets and approaches to effectively target the molecular drivers of invasion. These therapies represent a significant unmet clinical need for improved outcome for glioblastoma patients. In this application, we describe high throughput screening (HTS) assays targeting the FERM domain on the non-receptor kinase Pyk2 and outline a chemical probe discovery program to develop potent small molecule drug-like compounds that specifically inhibit Pyk2 activity. The proposed application is innovative for the development of methods for expression and purification of recombinant Pyk2 FERM domain, biochemical HTS assays, and cell based assays for the identification of small molecules inhibitors of Pyk2 that target the Pyk2 regulatory FERM domain.|
|Grant #||1 R01 CA201303|
|FOA #||PAR 14-284|
|Title||High throughput screen to identify inhibitors of the Golgi GOLPH3 pathway|
|Prebys Lead||Jackson, M|
|Description||GOLPH3 is unique in being an oncogene, driving a high proportion of human cancers, that function at the Golgi in secretory trafficking. Thus, the GOLPH3 pathway that we discovered provides a unique opportunity to gain insight into the mechanisms that drive cancer and offers novel targets for therapeutics. Here we propose a high throughput screen to identify inhibitors of the Golgi GOLPH3 pathway to serve as tools to study cancer and as lead compounds for novel cancer therapeutics.|
|Grant #||1 R01 NS092955|
|FOA #||PAR 14-284|
|Title||TROY HTS Compound Screening|
|Prebys Lead||Jackson, M|
|Description||Glioblastoma is a leading cause of CNS tumor-related death and current therapy is largely ineffective due to local brain invasion. The proposed activity will bring together an interdisciplinary team of established academic and nonprofit institutes with a clinically relevant target, TROY, and state-of-the-art HTS facility with the requisite expertise to implement HTS-ready assays for the discovery and development of small molecule chemical probes. Discovery and development of small molecule chemical probes against the TROY signaling axis is the first step to developing new therapeutic strategies for effective clinical management of GB.|
|Grant #||1 R01 CA201226|
|FOA #||PAR 14-284|
|Title||High Throughput Screening to Discover Chemical Inhibitors of Quiescin Sulfhydryl Oxidase 1|
|Collaborator||Doug Faigel/Doug Lake|
|Institute||Mayo-AZ & ASU|
|Prebys Lead||Sergienko, E|
|Description||Quiescin Sulfhydryl Oxidase 1 (QSOX1) is an enzyme that is overexpressed by several malignancies including ductal pancreatic adenocarcinoma and breast cancer and is important for cancer cell growth and invasion. There are no known chemical inhibitors of QSOX1. In this study we will use HTS to identify novel inhibitors ofQSOX1 and confirm their activity in cancer cell-line assays of proliferation, reactive oxygen species, and invasion. A chemical inhibitor of QSOX1 will be useful for understanding the role of QSOX1 in normal development and cellular function and have promise as cancer chemotherapy.|
Infectious and inflammatory diseases grant awards
|Grant #||1R01 GM110119|
|Title||Discovery of Chemical Probes for an RNA-Binding Protein Host Defense Factor|
|Prebys Lead||Pinkerton, A|
|Description||The goal of this collaborative proposal between OyaGen, Inc and Sanford/Burnham is to synthesize and validate novel chemical scaffolds as molecular antagonists of APOBEC3G (A3G) binding to cellular RNAs. These probes will enable a direct test of the hypothesis that A3G RNA binding prevents the robust host defense activity present in cells and which is necessary to overcome an HIV infection. The controversy of whether A3G DNA mutagenic activity is sufficient to protect the population from an HIV infection and progression to AIDS has deterred the pharmaceutical industry from engaging on this innovative drug target. Our probes are therefore an important first step in the development of lead drug compounds that will have high value for HIV/AIDS prevention and rescue therapy for those infected with multidrug resistant strains of HIV.|
|Grant #||1 R01 AI104916|
|Title||Selective Inhibitors of Plasmodium Falciparum G6PD as Novel Antimalarials|
|Prebys Lead||Pinkerton, A|
|Description||Every year, tropical malaria is responsible for nearly one million deaths, and the malaria-causing parasite is rapidly developing resistance against most clinically available drugs, which drives the urgent need for novel antimalarials. Glucose-6-phosphate dehydrogenase (G6PD) is a novel target for antimalarial drug design based on observations that humans with a deficiency in this enzyme are protected from malaria. We have generated selective probes against the parasite version of this enzyme and aim to optimize these probes towards the development of novel antimalarial drugs.|
|Grant #||1 R21 AI122845|
|FOA #||PAR 13-303|
|Title||Binding Interface of HIV Vif and APOBEC3G as a Therapeutic Target|
|Prebys Lead||Jackson, M|
|Description||APOBEC3G (A3G) is an antiviral protein found in human hosts that works by inducing rapid mutations in HIV viral genome and causing it to fail during replication. However, in response, HIV turns on the Vif protein, which binds to A3G and thereby triggers its elimination by the host's intracellular protein digestion machinery. Despite significant academic research, there is an unmet need to identify small molecular antagonists of Vif that have clinical potential. We have developed a markedly different, biophysically based high-throughput approach to screen for compounds that block Vif's interactions with A3G directly, thereby protecting A3G from Vif-dependent degradation. Our studies will afford the potential to find compounds with a novel mode-of-action and pharmacologic properties that enable new drug development of this untapped antiviral target.|
|Grant #||1 R01 AI125609|
|FOA #||PAR 13-364|
|Title||HTS Assay for P. falciparum apicoplast glutamyl-tRNA synthetase|
|Institute||J. Craig Venter Institute|
|Prebys Lead||Jackson, M|
|Description||There are approximately 200 million malaria cases and 500,000 deaths due to malaria every year. This research will develop and validate a high-throughput laboratory test that can be deployed on a large-scale to identify compounds that inhibit a parasite-specific metabolic pathway that we identified in the malaria parasite's apicoplast. The validated test will be invaluable in subsequent efforts to develop new pharmaceuticals that kill malaria parasites by specifically obstructing the targeted metabolic pathway.|
Cardiovascular and metabolic diseases grant awards
|Grant #||1 R01 DK106233|
|Title||Small molecule inhibitors of LMPTP: an obesity drug target|
|Prebys Lead||Pinkerton, A|
|Description||Diabetes due to reduced sensitivity of tissues to insulin is responsible for much of the increased morbidity and mortality associated with obesity. This grant application is focused on LMPTP, a regulator of insulin action and a candidate drug target for treatment of obesity-associated diabetes. Our goal is to develop a specific small-molecule inhibitor of LMPTP to validate this enzyme as a drug target for obesity-associated diabetes.|
|Grant #||1 R01 DK106512|
|Title||Podocyte-based HCS assays for discovering therapeutics against kidney diseases|
|Prebys Lead||Heynen-Genel, S|
|Description||Chronic kidney disease (CKD) affects over 10% of all adults, and is common in patients with diabetes, hypertension and heart disease. We have limited treatment options available for patients with CKD, which is mostly managed using drugs to for blood pressure. We have recently developed a novel high throughput screening assay that will allow us to identify and develop novel, kidney-directed therapeutics for CKD. We believe that the proposed studies will herald a new generation of therapeutics to treat various kidney diseases.|
|Grant #||1 R01 DK103850|
|Title||Small Molecule Discovery for GC-A Activators|
|Prebys Lead||Malany, S|
|Description||The natriuretic peptide GC-A receptor possesses pleiotropic beneficial properties in multiple organs and cell types, which may protect against cardiovascular and metabolic disease. There are no small molecule, non- peptide, drugs in existence to activate this receptor and bring improved therapeutics to these devastating diseases. This application seeks, for the first time, to provide discovery of such a novel therapeutic small molecule targeting GC-A.|
|Grant #||1 R01 DK105010|
|FOA #||PAR 14-284|
|Title||Identifying CXCR4 Receptor Agonists to Improve Diabetic Healing|
|Prebys Lead||Malany, S|
|Description||Complications of diabetes lead to impaired skin integrity and delayed wound healing, resulting in increased hospitalizations and added healthcare expense, exceeding $1.5 billion dollars annually for just diabetic foot ulcers. We have demonstrated that the impaired integrity of diabetic skin and impaired healing in diabetic wounds is associated with decreased SDF-1? production and abnormal microRNA gene expression. We have shown that treatment of diabetic skin and wounds with SDF-1? corrects these impairments, and our overall goal is to identify small molecule agonists to the SDF-1? receptor CXCR4 to improve the integrity of diabetic skin and prevent injury, as well as to improve the healing of diabetic wounds once they occur.|
The Prebys Center is a fully capable early drug discovery research operation with a strong track record of collaboration, high grant success rates and productive research.
Neurotensin (NT), a neuropeptide that acts as a regulator of many important systems including the dopaminergic system, has a broad spectrum of physiological activities: acting as a neurotransmitter in the brain; behaving as a digestive hormone in the gut; and acting as a regulator of cardiac output and blood pressure in the cardiovascular system. Therapeutic rationale have been proposed for brain penetrant NTR1 (neurotensin receptor 1) agonists for the treatment of schizophrenia, addiction and obesity, and indeed, an increasing body of preclinical and clinical evidence supports the promise of NT analogs as therapeutic agents for schizophrenia, psychostimulant abuse, and obesity. Our NTR1 research program was born from a collaboration with Duke University researchers Larry Barak and Marc Caron. Funding from NIH’s Molecular Libraries Program stimulated our initial investigations, which have continued through other mechanisms.
- PCT WO 2015200534 “Preparation of substituted quinazolines as small molecule agonists of neurotensin receptor 1” Pinkerton, A. B.; Hershberger, P. M.; Peddibhotla, S.; Maloney, P. R.; Hedrick, M. P.
- PCT WO 2014100501 “Small Molecule Agonists Of Neurotensin Receptor 1” Pinkerton, A.; Maloney, P.; Hershberger, P.; Peddibhotla, S.; Hedrick, M.; Barak, L.; Caron, M.
- Lead optimization of brain penetrant Neurotensin Receptor 1 agonists, Anthony Pinkerton Renewed as an R33 development award
- Drug Abuse: Discovering Ligands for Pertinent GPCRs , Collaboration with Marc Caron at Duke University and Anthony Pinkerton at SBP
- Small Molecule Agonsists for the Neurotensin 1 Receptor, Collaboration with Lawrence Barak at Duke University and Anthony Pinkerton at SBP
The glucocorticoid receptor (GR) is a member of the nuclear receptor super-familyof transcription factors. Some GR chaperones have been genetically linked to mooddisorders, PTSD and actions of mood stabilizers. Further, the most well characterized GR polymorphisms support a positive association between reduced GC sensitivity and beneficial metabolic and cognitive effects. The objective of the GR program is to develop antagonists of the HPA Axis and Inflammatory
- PCT WO 2016123392 “Pyrazolopyridines as inhibitors of glucocorticoid receptor translocation” Pinkerton, A. B.; Hassig, C. A.; Jackson, M. R.; Ardecky, R. J.; Pass, I.
Malignant melanoma is a rapidly metastasizing tumor notoriously unresponsive to common therapies. The eIF4 research program, originating in the laboratory of Dr. Ze’ev Ronai, seeks to develop a novel class of inhibitors that targets a key component in the translation initiation complex, and which specifically treat BRAFi-resistant and BRAF-WT melanomas.
- PCT WO 2016140973 “Quinolinones as inhibitors of translation initiation complex” Ronai, Z.; Pinkerton, A. B.; Feng, Y.; Topisirovic, I.; Brown, K.; Hassig, C. A.
This research program is funded by the Chemical Biology Consortium, and originates in the lab of Dr. Michael Lieber at the University of Southern California.Together with the consortium, we are exploring the role of Artemis in cancer, and its potential as a therapeutic.
- Selective Inhibitors of the Artemis Endonuclease, Collaboration with Michael Lieberat the University of Southern California CBC
Metabolism and cardiovascular disease
Medial vascular calcification causes generalized arterial calcification of infancy, a severe childhood disease, and is an increasingly recognized problem in patients with diabetes, chronic kidney disease and other serious conditions. Calcification is associated with significant morbidity and mortality in these diseases and currently there are no effective treatments. Our TNAP research program investigated the pathophysiological and therapeutic role of this phosphatase.
- Lead Optimization of Novel Inhibitors of Tissue Non-specific Alkaline Phosphatase, Collaboration with Nick Cosford and Jose Luis Millan
One of the pathological hallmarks of diabetic retinopathy (DR)— the most common diabetic eye disease and a leading cause of blindness in the US—is the development of immature, fragile blood vessels on the retina. This process, called angiogenesis, isstimulated by pro-angiogenic molecules such as vascular endothelial growth factorand apelin. Apelin is a newly discovered protein shown to play a critical role in thedevelopment of blood vessels. Several lines of evidence suggest that blocking apelinin the eye would be a successful treatment for DR, which is what we are investigating in this research program.
- PCT WO 2015184011 “Agonists of the apelin receptor and methods of use thereof” Pinkerton, A. B.; Smith, L. H.
- US 20140005181 “Small molecule antagonists of the apelin receptor for the treatment of disease” Smith, L. H.; Pinkerton, A. B.
Protein tyrosine phosphatases (PTPs) are key regulators of metabolism and insulin signaling. As a negative regulator of insulin signaling, the low molecular weight protein tyrosine phosphatase (LMPTP) is a promising drug target for insulin resistance and related conditions. Inhibitors developed at the Prebys Center, incollaboration with Dr. Nunzio Bottini currently at UC San Diego, have the potential for therapeutic development for the treatment of obesity-associated insulin resistance and heart failure.
- PCT WO 2016061280 “Inhibitors of low molecular weight protein tyrosinephosphatase and uses thereof” Anthony B. Pinkerton, Thomas Chung, MichaelHedrick, Robert John Ardecky, Nunzio Bottini, Jiwen Zou, Santhi R. Ganji, Stephanie Stanford, Kenneth E. Jenkins
- Small Molecule Inhibitors of LMPTP: An Obesity Drug Target, R01 Collaboration with Nunzio Bottini of UC San Diego and Anthony Pinkerton of SBP
- Small Molecule Inhibitors of LMPTP: An Obesity Target, R03 Collaboration with Nunzio Bottini of UC San Diego and the Conrad Prebys Center for Chemical Genomics
Immunology and infectious disease
During antibody responses, B cells undergo a series of migratory events that guide them to the appropriate micro environments for activation and differentiation. EBI2 plays an important role in coordinating rapid versus long term humoral responses as proliferating B cells begin to follow one of two alternate fates: differentiation into plasma cells or germinal center (GC) B cells. Several studies linked EBI2 expression to human neoplastic diseases, such as acute myeloid leukemia, chronic lymphocytic leukemia and diffuse large B cell lymphoma. In collaboration with Robert Rickert, the EBI2 research program has investigated mechanisms by which perturbations in EBI2 effect immune-mediated inflammatory disease.
- Functional Antagonists of EBI2/GPR183 as Chemical Probes for Inflammation, Collaboration with Robert Rickert and the Conrad Prebys Center for Chemical Genomics
Glucose-6-phosphate dehydrogenase (G6PD) is a novel target for antimalarial drug design based on observations that humans with a deficiency in this enzyme are protected from malaria. Working together with Lars Bode, of the University ofCalifornia, we are investigating the development of novel antimalarial drugs, which induce the same resistance in people who do not naturally have deficiencies inG6PD.
- Selective Inhibitors of Plasmodium Falciparum G6PD as Novel Antimalarials, Collaboration with Lars Bode of UC San Diego and Anthony Pinkerton of SBP
- Identification of G6PD inhibitors for the development of novel antimalarial drugs, Collaboration with Lars Bode of UC San Diego and Edaurd Sergienko of SBP
Ectopic calcification in pseudoxanthoma elasticum responds to inhibition of tissue-nonspecific alkaline phosphatase.
Ziegler SG, Ferreira CR, MacFarlane EG, Riddle RC, Tomlinson RE, Chew EY, Martin L, Ma CT, Sergienko E, Pinkerton AB, Millán JL, Gahl WA, Dietz HC
Sci Transl Med 2017 Jun 7 ;9(393)
TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling.
Masyuk TV, Masyuk AI, Lorenzo Pisarello M, Howard BN, Huang BQ, Lee PY, Fung X, Sergienko E, Ardecky RJ, Chung TDY, Pinkerton AB, LaRusso NF
Hepatology 2017 Oct ;66(4):1197-1218
Characterization of the Zika virus two-component NS2B-NS3 protease and structure-assisted identification of allosteric small-molecule antagonists.
Shiryaev SA, Farhy C, Pinto A, Huang CT, Simonetti N, Elong Ngono A, Dewing A, Shresta S, Pinkerton AB, Cieplak P, Strongin AY, Terskikh AV
Antiviral Res 2017 Jul ;143:218-229
A cellular target engagement assay for the characterization of SHP2 (PTPN11) phosphatase inhibitors.
Romero C, Lambert LJ, Sheffler DJ, De Backer LJ, Raveendra-Panickar D, Celeridad M, Grotegut S, Rodiles S, Holleran J, Sergienko E, Pasquale EB, Cosford NDP, Tautz L
J Biol Chem 2020 Jan 17 ;
Discovery of small molecule antagonists of chemokine receptor CXCR6 that arrest tumor growth in SK-HEP-1 mouse xenografts as a model of hepatocellular carcinoma.
Peddibhotla S, Hershberger PM, Jason Kirby R, Sugarman E, Maloney PR, Hampton Sessions E, Divlianska D, Morfa CJ, Terry D, Pinkerton AB, Smith LH, Malany S
Bioorg Med Chem Lett 2020 Feb 15 ;30(4):126899
Mechanisms Underlying the Hyperexcitability of CA3 and Dentate Gyrus Hippocampal Neurons Derived From Patients With Bipolar Disorder.
Stern S, Sarkar A, Stern T, Mei A, Mendes APD, Stern Y, Goldberg G, Galor D, Nguyen T, Randolph-Moore L, Kim Y, Rouleau G, Bang A, Alda M, Santos R, Marchetto MC, Gage FH
Biol Psychiatry 2019 Oct 1 ;
Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators.
Pinkerton AB, Peddibhotla S, Yamamoto F, Slosky LM, Bai Y, Maloney P, Hershberger P, Hedrick MP, Falter B, Ardecky RJ, Smith LH, Chung TDY, Jackson MR, Caron MG, Barak LS
J Med Chem 2019 Sep 12 ;62(17):8357-8363
Gardell SJ, Hopf M, Khan A, Dispagna M, Hampton Sessions E, Falter R, Kapoor N, Brooks J, Culver J, Petucci C, Ma CT, Cohen SE, Tanaka J, Burgos ES, Hirschi JS, Smith SR, Sergienko E, Pinkerton AB
Nat Commun 2019 Jul 19 ;10(1):3241
Krieg R, Jortzik E, Goetz AA, Blandin S, Wittlin S, Elhabiri M, Rahbari M, Nuryyeva S, Voigt K, Dahse HM, Brakhage A, Beckmann S, Quack T, Grevelding CG, Pinkerton AB, Schönecker B, Burrows J, Davioud-Charvet E, Rahlfs S, Becker K
Nat Commun 2019 Jul 8 ;10(1):2997