Modulateurs d'enzymes

Inhibitor of dihydroorotate dehydrogenase; anti-inflammatory; immunomodulatory

Forskolin is a compound derived from the medicinal plant Coleus forskohlii. As an activator of adenylate cyclase, Forskolin causes increases cellular levels of cAMP, and can be used in cell physiology research. It also has antihypertensive, platelet aggregation inhibitory and smooth muscle relaxant effects.

NButGT (N-butyryl-glucosamine-1,5-lactone O-(phenylcarbamoyl)oxime) is a selective inhibitor of O-GlcNAcase (OGA), the enzyme responsible for removing O-linked N-acetylglucosamine (O-GlcNAc) modifications from proteins. It effectively increases O-GlcNAc levels in cells and tissues without altering hexosamine biosynthetic pathway enzyme expression. It has also been shown that NButGT rapidly increases O-GlcNAcylation of mitochondrial proteins involved in oxidative phosphorylation and metabolism. While effective, NButGT served as a precursor to more potent OGA inhibitors like Thiamet-G. These findings highlight NButGT's importance as a tool for studying O-GlcNAcylation in various biological contexts, particularly in cardiac and neurological research. For example, in recent cardiac studies, NButGT pretreatment has demonstrated an improvement in cardiac output and mitochondrial respiration when combined with epinephrine.

Inhibits phorbol ester TPA/PMA; immunosuppressant

Inhibitor of CDK4/6 serine/threonine kinases; antineoplastic

Potent and selective MAP/ERK kinase 1/2 inhibitor. Reduces growth of tumor cells with B-Raf and Ras mutations. Tumor regression observed after chronic treatment in in vivo xenograft models. Enhances anti-tumor effect in combination with irinotecan or docetaxel.

Inhibits multiple receptor tyrosine kinases (RTKs), including c-Kit, PDGFRβ, PDGFRα, c-Met, and Axl. Sitravatinib inhibits proliferation of sarcoma cells and reduced tumor growth in vivo. Promotes immune response in tumor microenvironment and enhances sensitivity to immune checkpoint inhibitors. This compound is undergoing several clinical trials as a potential anti-cancer therapeutic agent.

Brinzolamide is a carbonic anhydrase inhibitor this is used for the treatment of ocular hypertension and glaucoma. Inhibition of carbonic anhydrase slows the formation of bicarbonate ions and as a result of this, it slows fluid flow in the eye, lowering the intraocular pressure. It has a high lipophilicity to enable diffusion across the blood-retinal barrier.

Inhibitor of PIP5K1C

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.

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

Inhibitor of CPT1 and CPT2 enzymes; inhibitor of mTORC1 kinase; anti-fungal

Ranolazine is a group P2 drug that reverses the pathogenic mechanism of myocardial infarction. It is used to treat chronic angina. It decreases myocardial wall tension and improves coronary blood flow. It inhibits the ryanodine receptor, which is responsible for regulating the release of intracellular calcium in cardiac and skeletal muscle cells. Furthermore, it is also effective at preventing atrial fibrillation and has been studied as monotherapy as well as in combination with other medications used to treat irregular heartbeat.

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.

Activator of soluble guanylyl cyclase (sGC) which stimulates cGMP production and is effective in cells under oxidative stress. Ataciguat stimulates the heme-free form of the sGC enzyme via the sGC N-terminus of β1-subunit. Ataciguat can promote vasorelaxation and hypotension by restoring or potentiating the nitric oxide (NO) signalling pathway.

Tadalafil analogue; PDE 5 inhibitor

Irreversible ErbB receptor tyrosine kinase inhibitor

GSK-126 is a potent inhibitor of histone lysine methyl transferase 2, which is encoded by the enhancer of zeste homolog 2 gene (EZH2). The EZH2 protein regulates cell cycle as it represses the Polycomb-Repressive Complex 2 (PRC2), allowing cells to divide actively. GSK-126 inhibits the EZH2 by targeting the catalytic domain (SET) of the enzyme and therefore blocks the PCR2 repression mechanism, resulting in cell proliferation arrest. The compound has shown therapeutic potential for a variety of cancers.

Inhibitor of mutant B-rafV600E protein that results in decreased proliferation of cancer cells with this mutation. Treatment of metastatic melanoma in patients harboring the V600E mutation, had improved disease outcome. This antitumor activity is enhanced when combined with MEK inhibitor trametinib.