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This technology includes the development and use of small molecules that inhibit O-linked beta-N-acetylglucosamine (O-GlcNAc) transferase (OGT) for a variety of pathologies, including Alzheimer's disease, cancer, cancer, diabetes, and neurodegenerative disorders the treatment of cancer and as a potential antiviral. OGT is a ubiquitous enzyme that catalyzes the transfer of N-acetylglucosamine (GlcNAc) to the serine or threonine residues of nuclear and cytoplasmic proteins.

This technology includes the use of proteasome inhibitors, such as Bortezomib, for the treatment of the most prevalent form of Charcot-Marie-Tooth disease type 1A (CMT1A). Duplication of the peripheral myelin protein 22 (PMP22) gene, normally involved in myelination of the peripheral nervous system, is the causative agent in most forms of CMT1A. A drug discovery program was initiated and found that proteasome inhibitors can be used to target PMP22.

This technology includes the use of pyridines for anticancer treatment. A common feature of cancer cells is a high level of reactive oxygen species with a concomitant increase of two antioxidative systems to combat the toxicity: the glutathione and thioredoxin systems. Inhibiting either, or both, of these systems is a promising avenue to target cancer cells. Thioredoxin Reductase 1 (Trxr1) is an important selenoprotein in the thioredoxin antioxidative system which has been implicated as a potential anti-cancer target.

This technology includes the discovery and use of novel selective 12-LO (lipoxygenase) inhibitors, 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives, for attenuating large clots and for the treatment of Type 1/2 diabetes. A 12-LO inhibitor could be a potent intracellular approach to block platelets from forming large clots in response to vessel injury or activation of the coagulation pathway, either due to diabetes and/or cardiovascular disease. Blocking clot formation can significantly decrease the occurrence of myocardial infarction and death.

NCATS has developed a highly diverse synthetic library that will allow for the rapid identification of novel nanobodies that bind to a wide arrange of target antigens. The humanized framework used to construct the library will facilitate the transition of lead candidates into patient studies. Several highly potent SARS-CoV-2 nanobodies (antibodies) have been identified and are available for further development.

NCATS is actively seeking licensing for the 1) a synthetic library and 2) the potent neutralizing antibodies with activity against SARS-CoV-2.

The invention provides two vascularized, multi-chip models for the alveoli and the small airway. Both models comprise a perfusable three-dimensional (3D) microvascular network consisting of human primary microvascular endothelial cells, fibroblasts, and pericytes with a differentiated lung epithelial layer exposed at the air-liquid interface (ALI) on top, built on a high-throughput, 64-chip microfluidic plate platform. The platform does not require the support of a permeable membrane and the epithelial cells are directly seeded on the perfused microvascular network.

Recent studies have identified the G-protein-coupled receptor (GPCR) for insulin-like 3 peptide (INSL3), relaxin family peptide receptor 2 (RXFP2), as an attractive target for the treatment of bone diseases such as osteoporosis and rare bone diseases such as osteogenesis imperfecta. Currently, the most effective available treatment for osteoporosis is an expensive hormone therapy that requires daily injections. A stable, orally deliverable drug is a much more desirable alternative. Our RXFP2 agonists perform as well as the natural ligand INSL3 in cellular assays.

This technology relates to the creation and use of newly identified ligands to the D1 dopamine receptor (D1R). The D1 dopamine receptor is linked to a variety of neuropsychiatric disorders and represents an attractive drug target for the enhancement of cognition in schizophrenia, Alzheimer disease, and other disorders. These ligands are positive allosteric modulators (PAMs) that bind to the dopamine receptor at a site other than where dopamine binds and causes the receptor to have an increased response.

This technology relates to the description and therapeutic use of a small molecule that selectively binds to and activates the D3 dopamine receptor. Dopamine receptors (DARs) are members of the G protein-coupled receptor (GPCR) superfamily that play a critical role in cell signaling processes, especially modulating the transfer of information within the nervous system. Members of the DAR subfamilies share high sequence homology, especially the D2 and D3 DARs. Most currently available dopaminergic drugs cross-react with both subtypes to varying degrees.

3D spheroids have emerged as powerful drug discovery tools given their high-throughput screening (HTS) compatibility. The present invention presents a method for generating functional neural spheroids with differentiated human induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes at cell type compositions mimicking specific regions of the human brain.