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This technology includes a series of novel benzene-1,4-disulfonamides that activate TRPML1 receptor. The TRPML1 receptor is a lysosomal Ca2+ channel that has been shown to be involved in controlling lysosome functions, among then the maintenance of the integrity of the plasma membrane and the modulation of autophagosome-lysosome fusion. The improved ability of the receptor to deliver Ca2+ ions to the cytosol had been correlated with its capacity to modulate autophagy and lysosome exocytosis.

This technology includes a new Zika virus NS-1 assay which was used for a compound screen. Because the NS-1 protein is synthesized only in the Zika virus replication stage, the inhibition of NS-1 protein level by compounds determined in this NS-1 assay indicates the inhibition of Zika virus replication in human cells. A total of 256 compounds have been identified as active compounds that inhibited NS-1 production in human cells that have the potential to be developed as new therapeutics for the treatment of infection with Zika virus.

This technology includes a new chemical series of substituted bicyclic heteroaryl small molecules as potent bromodomain-containing protein BRD4 inhibitors used for the treatment of cancer and inflammatory diseases. The optimization led to compounds with good potency in enzymatic assay ( 100 nM) and in MV4-11 cell-based assay ( 1000 nM) as well as excellent early ADME properties. We also identified N-methyl 2 pyridone and N-methyl pyrrolopyridone are great replacements of di-methylisoxazole. This chemical series also exhibited good ADME profiles, including PK.

This technology includes a family of inhibitors of 3-phosphoglycerate dehydrogenase (PHGDH) which could be utilized as a treatment for cancer. These compounds are based on a carbiothioamide core and represent the first chemotype capable of inhibiting this enzyme. The compounds have in vitro IC50s of 1-5 uM and exhibit selective cytotoxicity towards PHGDH-overexpressing cell lines of ~10 uM. They exhibit at least an order of magnitude lower toxicity towards cell lines that do not express PHGDH.

This technology includes compounds that improve endoplasmic reticulum-lysosomal trafficking and normalizes the Niemann-Pick type C (NPC) phenotype in assays using NPC1 patient cells, which can be used for the treatment of NPC, other lysosomal storage disorders, and potentially other neurodegenerative disorders. NPC is a rare neurodegenerative lipidosis caused by mutations in NPC1 or NPC2 genes, and characterized by the accumulation of cholesterol and glycolipids in the late endosomes and lysosomes. Currently there is no FDA-approved treatment for this devastating neurodegenerative disease.

This technology includes the design, synthesis, and use of a novel chemical series for multiple treatments, including for treating cancer. A series of substituted bicyclic heteroaryl small molecules were found to be a potent inhibitor of bromodomain-containing protein 4 (BRD4) for multiple uses, including cancer. A BRD4 inhibitor is in a class of drugs known as BET inhibitors that are used broadly as anti-inflammatories and as anti-cancer agents. The chemical series exhibited less hepatocyte toxicity compared to existing treatments.

This technology includes the creation and use of compounds, including kinetin derivatives, that improve mRNA splicing in a cell for the treatment of disorders associated with misspliced mRNA, including familial dysautonomia (FD). FD, the best-known and most common member of a group of congenital sensory and autonomic neuropathies, affects neuronal development and is associated with progressive neuronal degeneration. This disease is caused by mutations in the splicing of intron 20 of the IKMKAP gene that results in a unique pattern of tissue-specific exon skipping.

This technology includes the use of novel lactate dehydrogenase (LDH) inhibitors, including WO2018005807A1, for the treatment of primary hyperoxalurias (PHs). PHs are rare autosomal recessive disorders caused by overproduction of oxalate, leading to recurrent calcium oxalate kidney stone disease, and in some cases end-stage renal disease. One potential strategy to treat PHs is to reduce the production of oxalate by diminishing the activity of LDH, the proposed key enzyme responsible for converting glyoxylate to oxalate.

This invention includes a novel high-throughput assay to identify orthosteric inhibitors blocking the Zika virus NS2B-NS3 protease. Pathogenic flaviviruses, including Zika, require the NS2B-NS3 protease for viral replication. There is currently an unmet need for specific antiviral therapeutics against the Zika virus. Preliminary screening using the NCGC Pharmaceutical Collection library identified a group of drugs including temoporfin, erythrosin B, niclosamide, and nitazoxanide that can significantly inhibit the interactions between NS2B and NS3.

This technology relates to the identification and use of a group of compounds that activate the AMP-activated protein kinase (AMPK) and also effectively reduce lysosomal cholesterol accumulation in patients with Niemann-Pick disease Type C (NPC). Clinical trials are currently underway to determine the efficacy of beta-cyclodextrin in treating patients with NPC. A potential mechanism has been proposed indicating that beta-cyclodextrin activated AMP-activated protein kinase, leading to restoration of autophagy in cells from NPC patients.