National Center for Advancing Translational Sciences (NCATS)

Novel and potent caspase 1 inhibitors are available for licensing. In particular, this technology discloses potent and selective caspase 1 inhibitors that target the active site of the enzyme. Caspase 1 is known to play a pro-inflammatory role in numerous autoimmune and inflammatory diseases and therefore represents an excellent target for treatment of a broad range of diseases, including but not limited to Huntington's, amyotrophic lateral sclerosis, ischemia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, and sepsis. Not surprisingly this enormous potential has resulted in at least three caspase 1 inhibitors entering clinical trials (VX-740, IDN-6556, and VX-765) in recent years.

Novel and potent caspase 1 inhibitors are available for licensing. In particular, this technology discloses potent and selective caspase 1 inhibitors that target the active site of the enzyme. Caspase 1 is known to play a pro-inflammatory role in numerous autoimmune and inflammatory diseases and therefore represents an excellent target for treatment of a broad range of diseases, including but not limited to Huntington's, amyotrophic lateral sclerosis, ischemia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, and sepsis. Not surprisingly this enormous potential has resulted in at least three caspase 1 inhibitors entering clinical trials (VX-740, IDN-6556, and VX-765) in recent years.

Cyclodextrins (CD), alone or in combination with other agents (e.g., vitamin E), as therapeutics for the treatment of lysosomal storage disorders (LSDs) caused by the accumulation of non-cholesterol lipids. CDs are sugar molecules in a ring form. The alpha-CD (6 sugars), beta-CD (7 sugars) and gamma-CD (8 sugars) are commonly used cyclodextrins. The hydroxypropyl-beta cyclodextrin (HPbCD) has been approved for pharmaceutical use. Recent reports show that beta-cyclodextrin including HPbCD and beta-methyl-cyclodextrin reduced cholesterol accumulation and neuronal cell loss in the mouse model of NPC1 disease. NCATS investigators found that CD (alpha-, beta- and gamma-CDs) increased intracellular Ca2+ and lysosomal exocytosis in both wild type cells and cells with Wolman disease, and reduced the size of enlarged lysosomes in six patient cell lines with LSDs. Further, CD in combination with tocopherol synergistically/additively reduced cholesterol accumulation in cells of NPC and Wolman diseases. Based on these results, they propose treatment of LSDs with cyclodextrins (such as alpha and gamma forms) alone or in combination with Vitamin E and its analogues for better efficacy and less side effects.

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 (AHF), 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.

This technology is a collection of small molecules screened for their ability to prevent or reduce the cytotoxic effects of the protein, Huntingtin. Huntington's disease is a neurodegenerative disorder due to a dominantly acting expansion of a CAG trinucleotide repeat in exon 1 of the Huntington (HTT) gene resulting in production of the altered (mutant) protein Huntingtin, which has a long chain of polyglutamine (poly Q) attached to the exon 1 encoded protein sequence. Clinical and statistical analyses have shown that an increased number of poly Q repetition correlates with the probability of developing the disease, with 36 to 40 being the accepted cut off number for developing the disorder with high probability. It is known that poly Q repetitions impact the physical properties of Huntingtin and cause it to produce aggregates that precipitate and form inclusion bodies, which are toxic to the neuronal cells. The compounds of this invention have been screened multiply in a neuronal cell model of Huntington’s disease containing anHTTwith an expanded repeat in exon 1 of 103 Qs for their ability to inhibit cytotoxicity and protein aggregation.

This technology is a collection of small molecules screened for their ability to prevent or reduce the cytotoxic effects of the protein, Huntingtin. Huntington's disease is a neurodegenerative disorder due to a dominantly acting expansion of a CAG trinucleotide repeat in exon 1 of the Huntington (HTT) gene resulting in production of the altered (mutant) protein Huntingtin, which has a long chain of polyglutamine (poly Q) attached to the exon 1 encoded protein sequence. Clinical and statistical analyses have shown that an increased number of poly Q repetition correlates with the probability of developing the disease, with 36 to 40 being the accepted cut off number for developing the disorder with high probability. It is known that poly Q repetitions impact the physical properties of Huntingtin and cause it to produce aggregates that precipitate and form inclusion bodies, which are toxic to the neuronal cells. The compounds of this invention have been screened multiply in a neuronal cell model of Huntington’s disease containing anHTTwith an expanded repeat in exon 1 of 103 Qs for their ability to inhibit cytotoxicity and protein aggregation.

The invention includes compounds and compositions for inhibiting phosphoglycerate mutase (PGM) activity. In some examples, the compounds selectively inhibit cofactor-independent PGM (iPGM). In particular embodiments, the compounds include one or more cyclic peptides. Co-factor independent phosphoglycerate mutase (iPGM) is an essential glycolytic enzyme and validated target in several infectious organisms structurally distinct from its human isozyme. iPGM, present in several types of parasitic roundworms, includingBrugia malayiandOnchocerca volvulus, infects roughly 150 million people living mostly in tropical regions. The parasites can cause devastating infectious diseases, such as river blindness. The enzyme also is found in bacteria, includingStaphylococcus aureus, which can cause the hospital-borne infection MRSA (methicillin-resistantStaphylococcus aureus), and anthrax. However, the enzyme has been considered “undruggable” due to unsuccessful attempts to identify inhibitors suitable for development from small molecule high throughput screening (HTS). As an alternative approach to HTS the exceedingly vast chemical space available from nucleic acid-encoded cyclic peptide libraries was used to isolate a potent and selective iPGM inhibitor class, called Ipglycermides. mRNA-display affinity selection was used to identify, enrich and decode high-affinity iPGM cyclic peptide ligands we termed Ipglycermides. Using solid phase peptide synthesis the ipglycermides and analogs were prepared in milligram quantity and evaluated in functional target-based assays on a panel of phosphoglycerate mutase enzymes from target and anti-target (i.e., human dPGM) species. The molecules were found to potently and selectively inhibit the catalytic activity of various microorganism iPGMs versus the human isozyme. The pharmacological evaluation of ipglycermide analogs and the binding site interaction revealed from an iPGM-ipglycermide co-crystal structure provide general molecular insights for the development of a therapeutic targeting this highly dynamic protein hereto now refractory toward inhibition by traditional small molecule ligands.

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. Thus, 12-hLO inhibition has the potential to attenuate platelet-mediated clot formation caused by diabetes and/or cardiovascular disease and significantly decrease the occurrence of myocardial infarction and death. Moreover, Type 1 and Type 2 diabetes are serious disorders that can lead to major complications and reduced lifespan. An unmet medical need is to identify new ways to protect beta cells in these metabolic disorders. A selective 12-hLO inhibitor could provide a new therapeutic approach to prevent or treat either form of diabetes.

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. The invention described here is a series of small molecules that activate pyruvate kinase (PK) isoform M2. PK-M2 is a critical metabolic enzyme that is affected in all forms of cancer. Inactivation of PK-M2 leads to a buildup of metabolic intermediates inside the cell. Tumor cells require a buildup of metabolic intermediates in order to undergo rapid cell growth and proliferation. Hence, activation of PK-M2 in tumor cells may prevent the buildup of metabolic intermediates and thereby stall tumor cell proliferation or destroy the tumor cells. Further, while in normal adult cells only PK isoforms R, L, or M1 are active, in all tumors only PK-M2 is active. Therefore, PK-M2 activation would affect only tumor cells, and small-molecule PK-M2 activators are not expected to be toxic to healthy cells. In addition, in patients with PK-R deficiency the buildup of metabolic intermediates in red blood cells ultimately leads to the loss of water from the cells and cell death. Small-molecule induced activation of PK-R in PK-deficient red blood cells may enhance vitality of these cells and decrease or eliminate enzyme-deficient hemolytic anemia in a patient.

Lactose, found in dairy products and other foods, is comprised of two simple sugars, glucose and galactose. In galactosemia, where galactose is not properly metabolized, build-up of toxic compounds, such as galactose-1-phosphate, can lead to liver disease, renal failure, cataracts, brain damage, and even death if this disorder is left untreated. Currently, the only treatment for galactosemia is elimination of lactose and galactose from the diet, but in some cases this is not sufficient to avoid long-term complications from the disorder. This technology describes selective small-molecule inhibitors of human galactokinase, which inhibit the first step in galactose metabolism. These compounds could be used to treat galactosemia by eliminating the build-up of toxic metabolites in brain, liver and other tissues, and could form the basis for the first effective treatment for this disorder. These inhibitors are also promising candidates for the treatment of certain cancers, such as PTEN/AKT misregulated cancers. The inventors have already shown that the inhibitors are cytotoxic for several cancer cell lines.