Moduladores enzimáticos

Natural anti-cancer agent; inhibitor of histone deacetylases

Inhibitor of p38 MAPK kinase

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.

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.

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.

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.

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.

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.

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.

Inhibitor of VEGF receptor tyrosine kinases and non-receptor tyrosine kinases

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.