DAta | National Center for Advancing Translational Sciences

ID	Title	Body
424	Invention E-134-2010/0	Selective 12-Human Lipoxygenase Inhibitors for the Treatment of Diabetes and Clotting Lead Inventor: David Maloney (NCATS) Inventors: Theodore Holman (University of California, Santa Cruz), Jerry Nadler (Eastern Virginia Medical School), Michael Holinstat (Thomas Jefferson University), Anton Simeonov (NCATS), Ajit Jadhav (NCATS) Ref. No.: E-134-2010/0 Abstract: This invention discloses small molecule inhibitors of human 12-lipoxygenase (12-hLO). 12-lipoxygenase expression, activation, and lipid metabolites have been implicated in type 1 and type 2 diabetes, cardiovascular disease, hypertension, Alzheimer's, and Parkinson's disease. The development of 12-hLO inhibitors may be a potent intracellular approach to decreasing the ability of platelets to form large clots in response to vessel injury or activation of the coagulation pathway. Publications: Protein Kinase C Regulation of 12-Lipoxygenase-Mediated Human Platelet Activation • Molecular Pharmacology • March 2012 • Probe Development Branch, NCATS Chemical Genomics Center Discovery of Potent and Selective Inhibitors of Human Platelet-Type 12-Lipoxygenase • Journal of Medicinal Chemistry • Aug. 11, 2011 • Probe Development Branch, NCATS Chemical Genomics Center 12-Lipoxygenase: A Potential Target for Novel Anti-Platelet Therapeutics • Cardiovascular & Hematologic Agents in Medicinal Chemistry • July 1, 2011 • Probe Development Branch, NCATS Chemical Genomics Center 12-Lipoxygenase Products Reduce Insulin Secretion and β-Cell Viability in Human Islets • Journal of Endocrinology and Metabolism • February 2010 • Probe Development Branch, NCATS Chemical Genomics Center Resistance to Type 1 Diabetes Induction in 12-Lipoxygenase Knockout Mice • Journal of Clinical Investigation • May 15, 1999 • Probe Development Branch, NCATS Chemical Genomics Center
423	Invention E-120-2010/0	Pyruvate Kinase M2 Activators for the Treatment of Cancer Lead Investigator: Matthew Boxer (NCATS) Inventors: Douglas Auld (NCATS), Craig Thomas (NCATS), Min Shen (NCATS) Ref. No.: E-120-2010/0 Abstract: NIH investigators have discovered a series of small compounds with the potential to treat a variety of cancers as well as hemolytic anemia. Contrary to most cancer medications, these molecules can be non-toxic to normal cells because they target a protein specific to the metabolic pathways in tumors, thus representing a significant clinical advantage over less-specific chemotherapeutics.
422	Invention E-109-2010/0	Arylthiazolyl Piperidines and Related Compounds as Modulators of Survival Motor Neuron (SMN) Protein Production Lead Inventor: Juan Marugan (NCATS) Inventors: Elliotn Adrophy (University of Massachusetts Medical School), Jonathan Cherry (University of Massachusetts Medical School), Noel Southall (NCATS) Steven Titus (NCATS), Jingbo Xiao (NCATS), Wei Zheng (NCATS) Ref. No.: E-109-2010/0 Abstract: This technology discloses compounds that modulate the amount of survival motor neuron protein (SMN). Low levels of SMN protein are associated with spinal muscular atrophy (SMA), which constitutes a group of inherited diseases that cause progressive muscle degeneration leading to death. Consequently, therapeutic inventions have focused on increasing SMN protein levels. This invention discloses novel arylthiazolyl piperidines, which are shown to be modulators of SMN production. This invention also discloses methods of treating SMA by administering SMN protein modulators. Publication: Discovery, Synthesis, and Biological Evaluation of Novel SMN Protein Modulators • Journal of Medicinal Chemistry • Sept. 22, 2011 • Probe Development Branch, NCATS Chemical Genomics Center
421	Invention E-094-2011/0	Inhibitors of Human Apurinic/apyrimidinic Endonuclease 1 (APE1), an Anticancer Drug Target Lead Inventor: David Maloney (NCATS) Ref. No.: E-094-2011/0 Abstract: APE1 is the primary mammalian enzyme responsible for the removal of abasic (AP sites) in DNA and functions as part of the base excision DNA repair pathway (BER). BER is instrumental in the repair of DNA damage caused by DNA alkylating agents (e.g. many cancer chemotherapeutics). APE1 has been shown to be overexpressed in cancer cells. It has been postulated that APE1 would be an attractive target in anti-cancer treatment paradigms; preclinical and clinical data confirm that APE1 is a valid anticancer drug target. Publications: Synthesis, Biological Evaluation, and Structure-Activity Relationships of a Novel Class of Apurinic/Apyrimidinic Endonuclease 1 Inhibitors • Journal of Medicinal Chemistry • April 12, 2012 • Probe Development Branch, NCATS Chemical Genomics Center Human AP Endonuclease 1 (APE1): From Mechanistic Insights to Druggable Target in Cancer • Cancer Treatment Reviews • August 2010 • Probe Development Branch, NCATS Chemical Genomics Center
420	Invention E-072-2012/0	Novel Small Molecule Agonists of the Relaxin Receptor as Potential Therapy for Heart Failure and Fibrosis Lead Inventor: Juan Marugan (NCATS) Inventors: Alexander Agoulnik (Florida International University), Catherine Chen (NCATS), Marc Ferrer-Alegre (NCATS), Noel Southall (NCATS), Jingbo Xiao (NCATS), Wei Zheng (NCATS) Ref. No.: E-072-2012/0 Abstract: The present invention is directed to novel small molecule agonists of the mammalian relaxin family receptor 1 (RXFP1), including human RXFP1. Activation of RXFP1 induces: 1) vasodilation due to up-regulation of the endothelin system; 2) extracellular matrix remodeling; 3) moderation of inflammation by reducing levels of inflammatory cytokines; and 4) angiogenesis. Small molecule agonists of RXFP1 may be useful in treating acute heart failure, scleroderma, fibrosis, other conditions associated with the biology of relaxin, and in improving reproductive health and wound healing. These compounds are the first and only small molecule agonists of RXFP1. Publications: Identification and Optimization of Small-Molecule Agonists of the Human Relaxin Hormone Receptor RXFP1 • Nature Communications • June 14, 2013 • Probe Development Branch, NCATS Chemical Genomics Center Identification of Small-Molecule Agonists of Human Relaxin Family Receptor 1 (RXFP1) by Using a Homogenous Cell-Based cAMP Assay • Journal of Biomolecular Screening • Dec. 4, 2012 • Probe Development Branch, NCATS Chemical Genomics Center
419	Invention E-070-2012/0	Novel Derivatives of Docosahexaenoylethanolamide as Therapeutics for Neuronal Disorders Lead Inventor: Juan Marugan (NCATS) Inventors: Erika Englund (NCATS), Hee-Yong Kim (NIAAA), Samarjit Patnaik (NCATS) Ref. No.: E-070-2012/0 Abstract: This technology provides derivatives of Docosahexaenoylethanolamide (synaptamide or DEA) which have increased potency and hydrolysis resistance as compared to DEA (structures of these derivatives are available upon request), as well as methods of using these derivatives to promote neurogenesis, neurite growth, and/or synaptogenesis. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid that accumulates in the brain during development, has been shown to play a key role in learning and memory development. Studies have also shown that DEA, a metabolite derived from DHA is very potent in accelerating neuronal growth and development. The inventors have discovered that the novel DEA derivatives they have designed are even more potent than DEA or DHA in accelerating neuronal growth, synaptogenesis and development. The inventors have shown that treatment of progenitor neural cells with some of these novel DEA derivatives leads to an increase in the amount of somatic neurons produced after differentiation. These novel compounds can be developed as therapeutics for conditions such as trauma, stroke, multiple sclerosis, Alzheimer's disease, brain and spinal cord injuries, and peripheral nerve injuries for rehabilitation. Publications: A Synaptogenic Amide N-docosahexaenoylethanolamide Promotes Hippocampal Development • Prostaglandins & Other Lipid Mediators • November 2011 • Probe Development Branch, NCATS Chemical Genomics Center N-Docosahexaenoylethanolamide Promotes Development of Hippocampal Neurons • Biochemical Journal • April 15, 2011 • Probe Development Branch, NCATS Chemical Genomics Center Docosahexaenoic Acid Promotes Hippocampal Neuronal Development and Synaptic Function • Journal of Neurochemistry • October 2009 • Probe Development Branch, NCATS Chemical Genomics Center
418	Invention E-050-2012/0	Cyclodextrins as Therapeutics for Lysosomal Storage Disorders Lead Inventor: Wei Zheng (NCATS) Inventors: Juan Marugan (NCATS), John McKew (NCATS), Manju Swaroop (NHGRI), Miao Xu (NHGRI) Ref. No.: E-050-2012/0 Abstract: Cyclodextrins, alone or in combination with other agents (e.g., vitamin E), as therapeutics for the treatment of lysosomal storage disorders caused by the accumulation of non-cholesterol lipids. Publications: δ-Tocopherol Reduces Lipid Accumulation in Niemann-Pick Type C1 and Wolman Cholesterol Storage Disorders • Journal of Biological Chemistry • Nov. 16, 2012 • Therapeutics for Rare and Neglected Diseases Evaluation of Cholesterol Reduction Activity of Methyl-β-Cyclodextrin Using Differentiated Human Neurons and Astrocytes • Journal of Biomolecular Screening • October 2012 • Therapeutics for Rare and Neglected Diseases
417	Invention E-043-2013/0	Highly Potent and Selective Deubiquitinating Enzyme Inhibitor Lead Inventor: Anton Simeonov (NCATS) Inventors: Thomas Dexheimer (NCATS), Ajit Jadhav (NCATS), Qin Liang (University of Delaware), David Maloney (NCATS), Andrew Rosenthal (NCATS), Zhihao Zhuang (University of Delaware) Ref. No.: E-043-2013/0 Abstract: Available for licensing are inhibitors that target the USP1/ UAF1 deubiquitinating enzyme (DUB) complex. The FDA approval and commercial success of Velcade®, a small molecule proteasome inhibitor, has established the ubiquitin-proteasome system (UPS) as a valid target for anticancer treatment. However, proteasome inhibitors in general suffer from a narrow therapeutic index and acquired resistance. A promising alternative to proteasome inhibition has been to target the enzymes upstream of proteasome-mediated protein degradation, i.e. the ubiquitin conjugation and deconjugation, to generate more specific, less toxic therapeutic agents. The investigators have developed small molecules that target the USP1/ UAF1 DUB complex that acts upstream of UPS and has been implicated in the DNA damage response. These compounds are the most potent and selective DUB inhibitors reported to date. Moreover, the inhibitors act synergistically with cisplatin, a DNA damaging anti-cancer drug, to overcome chemoresistance and enhance cytotoxicity. These results suggest the inhibitors may also improve the efficacy and potency of other commonly prescribed chemotherapeutic agents that are known to induce DNA damage.
416	Invention E-041-2010/0	Small Molecule Neuropeptide S (NPS) Antagonists for the Treatment of Addictive Disorders, Mood and Anxiety Disorders, and Sleep Disorders Lead Inventor: Juan Marugan (NCATS) Inventors: Markus Heilig (NIAAA), Ke Liu (NHGRI), Samarjit Patnaik (NCATS), Noel Southall (NCATS), Wei Zheng (NCATS) Ref. No.: E-041-2010/0 Abstract: The inventors have developed NPSR antagonists that hold the potential for being clinically useful treatments for alcohol and drug addiction. Publications: A Novel Brain Penetrant NPS Receptor Antagonist, NCGC00185684, Blocks Alcohol-Induced ERK-Phosphorylation in the Central Amygdala and Decreases Operant Alcohol Self-Administration in Rats • Journal of Neuroscience • June 12, 2013 • Probe Development Branch, NCATS Chemical Genomics Center Neuropeptide S Facilitates Cue-Induced Relapse to Cocaine Seeking Through Activation of the Hypothalamic Hypocretin System • PNAS • Nov. 9, 2010 • Probe Development Branch, NCATS Chemical Genomics Center Selective Modulation of Gq/Gs Pathways by Naphtho Pyrano Pyrimidines as Antagonists of the Neuropeptide S Receptor • ACS Chemical Neuroscience • Aug. 18, 2010 • Probe Development Branch, NCATS Chemical Genomics Center
415	Tox21 Nuclear Receptor Assays	Nuclear receptors (NRs) play critical roles in human development, metabolic homeostasis and reproduction. Inappropriate activation of nuclear receptors by environmental chemicals can lead to a broad spectrum of negative health effects. To evaluate environmental chemicals’ effects on endocrine disruption, Tox21 researchers have selected appropriate NR assays for quantitative high-throughput screening (qHTS). As a proof-of-concept study, researchers profiled in qHTS format approximately 3,000 environmental chemicals against a panel of 10 human NRs during the Tox21 pilot phase. The team evaluated these data from a chemical genomics point of view, in addition to assessing data reproducibility as a measure of data quality and applicability for down-stream analyses. This graphic describes how NRs interact with genes. NRs recognize small hormones or synthetic (man-made) compounds. Each NR activates genes that cooperate to change human physiology. This graphic shows example structure classes with consistent NR activity patterns or signatures. Compounds were clustered by similar structure using the SOM algorithm. Compounds in the same cluster belong to the same structure class. The structure classes shown in this figure contain compounds with similar activity patterns as well.

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