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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.

This technology describes a series of small-molecule activators of the pyruvate kinase M2 isoform (PK-M2).

This technology includes small molecule inhibitors of the cdc2-like kinase (Clk) and Dyrk kinase which can restore splicing outcomes within many dysregulated splicing events potentially reversing phenotypes associated with diseases associated with abnormal splicing. The Clks regulate the alternative splicing of microtubule-associated protein tau and are implicated in frontotemporal dementia and Parkinson's disease through the phosphorylation of splicing factors (SF).

This technology includes the identification and use of 12/15-lipoxygenase (LOX) inhibitors, including ML351 and related analogs, for post-stroke treatment. The 12/15-LOX directly oxidizes lipid membranes leading to their direct attack. After a stroke, the activity of 12/15-LOX is upregulated and is thought to contribute to increased neuronal loss and blood-brain barrier leakage. A high-throughput screen was undertaken to find inhibitors, which were then subjected to medical chemistry optimization.