Enzyme Modulators

<p>Natural anti-cancer agent; inhibitor of histone deacetylases</p>

<p>Bortezomib is a selective and reversible inhibitor of the multicatalytic 26S proteasome. The inhibition of protein breakdown affects several metabolic pathways and leads to cell death. The compound is effective in treating t-cell lymphomas and multiple myeloma because it prevents the binding of myeloma cells to bone marrow stroma and inhibits osteoclast differentiation.</p>

<p>Indirubin is a chemical compound that belongs to the indole family. It has been studied for its anti-inflammatory and antipyretic properties. Research suggests that Indirubin can inhibit certain kinases displaying antineoplastic properties.</p>

<p>Inhibitor of GSK3 kinase; activator of Wnt signalling</p>

<p>Inhibitor of p38 MAPK kinase</p>

<p>Mitochondrial division inhibitor (mdivi-1) inhibits dynamin related protein-1 (drp1)-dependent mitochondrial fission. It is a therapeutic candidate for the treatment of stroke, myocardial infarction and neurodegenerative disease. The neuroprotective effects of mdivi-1 has been demonstrated in various models of brain ischemia and neurodegeneration.</p>

<p>Inhibitor of sodium/potassium ATP-ase; anti-arrhythmic</p>

<p>Gemcitabine is as a synthetic pyrimidine nucleoside prodrug. The hydrogen atoms on the 2' carbon of deoxycytidine are replaced by fluorine atoms. Gemcitabine works by being incorporated into the DNA of cancer cells during replication and inhibiting DNA synthesis. First gemcitabine is converted into its active form, gemcitabine triphosphate, by cellular enzymes including deoxycytidine kinase (DCK), after it is taken up by cancer cells. The gemcitabine triphosphate interferes with the normal functioning of the enzymes involved in replicating DNA, leading to the termination of DNA synthesis and ultimately, cell death. Gemcitabine is used as a chemotherapy drug used to treat various types of cancer, including pancreatic, lung, breast, and ovarian cancer.</p>

<p>Nicotinamide phosphoribosyl transferase (NAMPT) competitive inhibitor with IC50 = 3.1 nM. A major consequence of NAMPT inhibition is the attenuation of glycolysis at the GADPH step because this enzyme requires NAD+ for activity. The compound exhibits broad spectrum anti-cancer activity and significant tumor regression was observed in vitro. Although retinal and haematological toxicity has been associated with NAMPT inhibitors, LSN 3154567 does not lead to retinopathy in rats and can be mitigated with co-administration of nicotinic acid.</p>

<p>Imatinib is a tyrosine kinase inhibitor that is used in the treatment of various leukemias and gastrointestinal stromal tumors. This drug inhibits the BCR-ABL tyrosine kinase. It is suggested that Imatinib also inhibits other tyrosine kinases such as PDGF, SCF and c-Kit.</p>

<p>Inhibitor of histone deacetylase 3 (HDAC3) with IC50 in nanomolar range. BRD 9908 was shown to preserve the insulin-secreting pancreatic cells in nonobese diabetic mice. BRD 3308 supressed infiltration of mononuclear cells and prevented β-cell death in vivo as well as increased basal insulin secretion in vitro. Studies on HIV infection models showed that HDAC3 inhibition by BRD 3308 disrupts the HIV latency by increasing the gene expression from HIV promoter.</p>

<p>Rapamycin is a macrolide antibiotic that has been studied as a potential anticancer agent. It binds to FK506 binding proteins (FKBPs) to form a complex that inhibits mammalian targets of rapamycin (mTOR). Rapamycin also blocks p70 S6 kinase activation by interleukin-2 and thereby inhibits proliferation of T cells. It induces differentiation of human pluripotent stem cells (hPSCs) to mesendoderm and blood progenitor cells.</p>

<p>Selective, potent, competitive and reversible inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) with IC50 of 2.3 nM and more than 10000-fold selectivity over the related 11β-HSD-2 isoform. BMS 823778 inhibits conversion of cortisone in cortisol and has applications in the treatment of diabetes type 2 since it can influence the occurrence of insulin resistance.</p>

<p>Irreversible blocker of three members of the ErbB family (ErbB1, ErbB2/HER2, and ErbB4) with IC50 in nanomolar range. The compound binds covalently to cysteine 797 residue in HER2 and blocks downstream cellular signalling, inhibits cellular growth and promotes apoptosis. Afatinib has been used for the treatment of tyrosine kinase inhibitor-resistant tumours with mutations in ErbB genes, especially for deletions in exon 19 and single nucleotide substitutions in exon 21. It has been used for treatment of non-small cell lung cancer (NSCLC), breast cancer, pancreatic cancer, colorectal cancer, etc.</p>

<p>Inhibits Mer receptor tyrosine kinase (IC50 = 4.3 nM). Selective over Axl (84-fold) and Tyro3 (58-fold). UNC 2881 inhibits phosphorylation of Mer kinase in 697 B-ALL cells (IC50 = 22nM). Inhibits EGF-induced activation of a chimeric enzyme, composed of EGFR fused with Mer. Blocks collagen-mediated platelet aggregation, implying the potential of this compound for treating thrombosis.</p>

<p>Selective inhibitor of the mutated RET variant RETV804M, which is the anticipated drug-resistant RET mutant that can occur in tumours treated with kinase inhibitors. The compound has a biochemical IC50 of 0.02 µM and selectivity for purified RETV804M over purified RET and KDR of 3.7 and 110, respectively. The efficacy of the compound was shown also in cell cultures with IC50 of 4.4 µM, and cell assay selectivity for RETV804M over RET and KDR of 0.89 and 2.3, respectively.</p>

<p>Inhibitor of VEGF receptor tyrosine kinases and non-receptor tyrosine kinases</p>

<p>Zorubicin hydrochloride is an anthracycline antibiotic, which is a derivative of daunorubicin, sourced from Streptomyces bacteria. This compound exhibits its mode of action primarily through intercalation into DNA, inhibiting the progression of the enzyme topoisomerase II. This interference prevents DNA replication and RNA synthesis, leading to apoptosis in rapidly dividing cells, making it a potent chemotherapeutic agent.</p>

<p>Cerivastatin is a drug that belongs to the class of drugs called statins. This drug is used to reduce the risk of cardiovascular events and lower lipid levels. Cerivastatin is an HMG-CoA reductase inhibitor and allows for a decrease in cholesterol in hepatic cells. Cerivastatin is cardioprotective and anti-atherosclerotic.</p>

<p>Protein kinase B (also known as RAC-alpha serine/threonine-protein kinase: Atk) is a serum and glucocorticoid-regulated protein kinase with three highly homologous isoforms (Akt1, 2 and 3). Akt1 and Akt3 are the predominant isoforms expressed in the brain, whereas Akt2 is mainly expressed in skeletal muscle and embryonic brown fat. These proteins play major regulatory roles in a range of physiological processes including: growth, proliferation, cell survival, angiogenesis, metabolism and Akt is also considered a proto-oncogene.This peptide (AKTide) is a selective substrate for these kinases and enables quick, easy and sensitive assays of Akt activity.</p>