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This technology includes the use of a beclin 1 inhibitor, 17-hydroxy Wortmannin, for the treatment of TRAIL-resistant colon cancer. TRAIL (TNF-related apoptosis-inducing ligand) binds to death receptors (DR4/DR5) and activates apoptosis in cancer cells. Multiple clinical trials have focused on promoting TRAIL-induced death but have had a lack of efficacy due to TRAIL resistance developing quickly in cancer cells. Recent work has found that this resistance may be mediated by a lack of activation of the apoptosis/autophagy regulator beclin 1.

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.

Methylmalonic Acidemia (MMA) is a metabolic disorder characterized by increased acidity in the blood and tissues due to toxic accumulation of protein and fat by-products resulting in seizures, strokes, and chronic kidney failure. A significant portion of MMA cases stem from a deficiency in a key mitochondrial enzyme, methylmalonyl-CoA mutase (MUT), required to break down amino acids and lipids. Currently, there are no treatments for MMA and the disease is managed primarily with dietary restriction of amino acid precursors and liver-kidney transplantation in severe cases.

Isolated Methylmalonic Acidemia (MMA) comprises a relatively common and heterogeneous group of inborn errors of metabolism. Most affected individuals display severe multisystemic disease characterized by metabolic instability, chronic renal disease, and neurological complications. Patients with the cobalamin A (cblA) subtype of MMA can have variable presentations, spanning the full spectrum of MMA associated symptoms and pathology, yet always harbor an element of clinical and biochemical responsiveness to injectable vitamin B12.

Cobalamin C deficiency (cblC) is the most common inborn error of intracellular cobalamin metabolism and is caused by mutations in MMACHC, a gene responsible for processing and trafficking dependent enzymes: intracellular cobalamin, resulting in elevated methylmalonic acid and homocysteine and methionine deficiency. Disease manifestations include growth failure, anemia, cardial defects and progressive blindness.

Isolated Methylmalonic Acidemia (MMA) and the related disorder Propionic Acidemia (PA) comprise a relatively common and heterogeneous group of inborn errors of metabolism. NHGRI scientist discovered that in isolated MMA, a novel inhibitory PTM, methylmalonyllysine, is generated and inactivates protein targets through the failure of SIRT-mediated deacylation, and identified a series of antibodies for PTM specificity.

Cobalamin C deficiency (cblC), caused by mutations in MMACHC, is the most common inborn error of intracellular vitamin B12 metabolism. NHGRI scientist have generated a number of Mmachc knockout mouse models. The cblC mice present with early lethality, recapitulate the neurological phenotype seen in patients, and have enabled proof of concept testing with traditional hydroxocobalamin formulations and doses. The scientist have also developed a novel combination of hydroxo- and methylcobalamin, having superior performance to traditional hydroxocobalamin only treatment.