Modulateurs d'enzymes

<p>Inhibits tankyrase (TNKS1 and TNKS2 with IC50 values of 11 and 4 nM respectively), by binding to the catalytic poly-ADP-ribose polymerase (PARP) domain. This stabilizes cytoplasmic protein Axin, mediating β-catenin depletion and thereby suppresses Wnt signalling pathway. XAV 939 has anti-proliferative and pro-apoptotic effects on neuroblastoma and colorectal cancer cells.</p>

<p>Histone acetyltransferase inhibitor of p300/CBP; anti-proliferative</p>

<p>Aminopterin is an antineoplastic agent and antifolate, which is a synthetic derivative of pteroylglutamic acid. It functions as a chemotherapeutic agent by inhibiting dihydrofolate reductase, an enzyme crucial in the folic acid pathway, thereby preventing the conversion of dihydrofolate to tetrahydrofolate. This disruption leads to impaired synthesis of purine nucleotides and thymidylate, which are essential for DNA synthesis and cell division.</p>

<p>Fluvastatin is a statin that lowers blood cholesterol and triglycerides by inhibiting HMG-CoA reductase, an enzyme that plays a critical role in the synthesis of cholesterol. Fluvastatin has also been shown to reduce the incidence of myocardial infarction, and to reduce atherosclerotic lesions in animal models, reducing the incidence of cardiovascular disease. Fluvastatin also has been shown to inhibit the activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS), which may be related to its anti-inflammatory effects. Furthermore, through lowering blood cholesterol, Fluvastatin also inhibits tubulointerstitial injury and prevents renal damage caused by high concentrations of the lipid.</p>

<p>Apixaban is an anticoagulant agent used for the prophylaxis of stroke and deep vein thrombosis leading to pulmonary embolism. This drug is an inhibitor of factor Xa and prothrominase. As a result, this prevents the formation of a thrombus.</p>

<p>Rosuvastatin is a drug that belongs to the group of statins. It is used for the treatment of high cholesterol and as an adjunct therapy for patients with coronary heart disease. Rosuvastatin reduces serum cholesterol by inhibiting HMG-CoA reductase, which is the rate-limiting enzyme in the production of cholesterol. Furthermore, this drug has been shown to have anti-inflammatory properties, which may be due to its ability to inhibit prostaglandin synthesis.</p>

<p>Inhibitor of folate synthesis; folic acid analogue</p>

<p>A potent and selective c-Met inhibitor. Anti-tumour activity demonstrated in xenograft models in vivo. Forms a thioether conjugate by reacting with thiol groups in proteins. Non-small-cell lung carcinoma (NSCLC) tumour cells that overexpress c-MET have increased sensitivity to AMG458.</p>

<p>H+/K+ ATPase inhibitor</p>

<p>Proteosome inhibitor; pro-apoptotic; has anti-myeloma activity</p>

<p>Phosphodiesterase inhibitor</p>

<p>Cis/trans-form of GK 563 [2351820-19-2]</p>

<p>R-(-)-Arundic acid is a chiral compound, which is a derivative of arundic acid specifically designed for enantiomeric purity. It is sourced through synthetic organic chemistry processes, allowing for precise control over its stereochemistry. The mode of action of R-(-)-Arundic acid involves the inhibition of astrocyte activation by modulating the synthesis of certain cytokines and inflammatory mediators. This mechanism provides a neuroprotective effect, making it a valuable tool in the study of neurodegenerative diseases and brain injuries.</p>

<p>Inhibitor of poly (ADP-ribose) polymerase enzyme; antineoplastic</p>

<p>Diacerein is a slow-onset anthraquinone IL-1 inhibitor that is used in the treatment of joint diseases such as osteoarthritis. This drug is also being studied for the treatment of insulin resistance and diabetes mellitus. Diacerein works to decrease inflammation and cartilage destruction by reducing the level of interleukin-1.</p>

<p>Cetilistat is a drug that is used to treat obesity. This drug inhibits the enzyme pancreatic lipase and so it prevents triglycerides from being hydrolyzed into absorbable free fatty acids.</p>

<p>Inhibitor of proteaseγ‐secretase, which allows to modulate of the activity of γ‐secretase substrates Notch, E-cadherin, ErbB4, and amyloid precursor protein (APP). The compound can inhibit the growth of tongue carcinoma cells by arresting cell cycle in G0–G1 phase, modulate the activity of Notch1 receptor and Caspase-3 protease and induce apoptosis. It was also demonstrated that this inhibitor reduces the levels of β-amyloid peptide in the brain of mice model for Alzheimer’s disease. This compound also enhances the neuronal differentiation embryonic cells.</p>

<p>Inhibitor of 8-oxoguanine DNA glycosylase OGG1 with IC50 of 0.059 μM and excellent specificity over other DNA repair enzymes. OGG1 and its substrate 8-oxoguanine are involved in mutagenesis, genotoxicity, inflammation and cancer. The compound can cause accumulation of 8-oxoguanine in DNA in vitro and is a potent tool for the study of OGG1 biology.</p>

<p>Inhibitor of tyrosinase in melanocytes: skin whitener</p>

<p>Casein kinase (CK1ε and CK1Ύ) inhibitor</p>

<p>Dual COX/5-LO inhibitor; anti-inflammatory; analgesic</p>

<p>Monoamine oxidase-B inhibitor; anti-parkinsonian; neuroprotective</p>

<p>AZD 1152 is an Aurora kinase inhibitor, which is a type of small-molecule therapeutic agent. It is derived from the pharmaceutical research conducted by AstraZeneca. Its primary mode of action involves the selective inhibition of Aurora B kinase, an enzyme crucial for the regulation of mitosis. By interfering with this enzyme, AZD 1152 disrupts the normal progression of cell division, leading to the inhibition of proliferation and induction of apoptosis in rapidly dividing cells.</p>

<p>An inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase that reduces total cholesterol and low-density lipoprotein (LDL). Cerivastatin is cardioprotective and anti-atherosclerotic. Cerivastatin inhibits the expression of the atherosclerotic genes monocyte chemoattractant protein-1 (MCP-1) and C-C chemokine receptor type 2 (CCR2), whilst inducing the expression of Kruppel-like factor 2 (KLF2).</p>

<p>MET tyrosine kinase inhibitor; anti-proliferative; pro-apoptotic</p>

<p>Omeprazole is a proton pump inhibitor (PPI) that inhibits the production of gastric acid in the stomach. This is due to Omeprazole binding through a stable disulphide bond to the H+/K+ ATPase enzyme found on parietal cells, and preventing hydrogen ion transport. Consequently, gastric acid secretion is supressed. As a PPI, Omerprazole can be used to treat disorders where gastric acid is over-secreted. Examples of these disorders are gastroesophageal reflux disease (GERD) and peptic ulcer disease.</p>

<p>Acecelofenac is a non-steroidal anti-inflammatory drug that is used in the treatment of osteoarthritis, arthritis, and ankylosing spondylitis. This drug is also a cyclooxygenase inhibitor and works by inhibiting this enzyme so that pain and inflammation is reduced.</p>

<p>Rivastigmine is a cholinergic agent that is used in the treatment of dementia in Parkinson’s and Alzheimer’s disease. This drug is a carbamate derivative that binds to and inactivates cholinesterase such as acetylcholinesterase and butyrylcholinesterase. This leads to an increase concentration of acetylcholine at cholinergic synapse.</p>

<p>An irreversible GSK-3β inhibitor that reduces phosphorylation of tau proteins, protects from neuronal loss and has cognitive and behavioural benefits in murine models. Studied for its potential as a therapeutic agent in Alzheimer’s disease and other neurodegenerative diseases. Tideglusib was also shown to inhibit the main protease Mpro from the SARS-CoV-2 virus with IC50 of 1.55 μM.</p>

<p>Inhibitor of chymotrypsin</p>

<p>A selective and potent inhibitor of phosphodiesterase 2 (PDE2). Raises cAMP and cGMP levels in neurons, improves social recognition and object memory in murine animals. Reverses anxiolytic effects induced by oxidative stress in mice by blocking cGMP-PKG signaling.</p>

<p>Inhibitor of immunophilin FKBP12 and mTOR signalling with immunosuppressant activity. Zotarolimus inhibits proliferation of endothelial cells and smooth muscle cells and is employed in vascular interventional therapies.</p>

<p>Rebamipide is a gastroprotective agent that is used to treat various gastrointestinal disorders such as gastric ulcers and GERD. This drug’s mechanism of action is not fully understood however, it is thought to exert its effects by promoting the secretion of protective mucus in the stomach and intestine, which helps to create a barrier against stomach acid and other irritants. Additionally, it has antioxidant and anti-inflammatory properties that can help reduce tissue damage.</p>

<p>Inhibits isocitrate dehydrogenase 1 (IDH-1) harbouring a gain of function mutation at R132, which causes impaired cellular differentiation via epigenetic modulation. By inhibiting mutant IDH1, synthesis of oncometabolite 2-hydroxyglutarate is reduced. This compound therefore has therapeutic potential in solid and haematological malignancies, such as acute myeloid leukemia (AML).</p>

<p>Inhibitor of FLT3 and AXL tyrosine kinases</p>

<p>BRK tyrosine kinase (PTK6) inhibitor; anti-proliferative in breast cancer cells</p>

<p>Inhibitor of leucine-rich repeat kinase LRRK2Â</p>

<p>Lovastatin is an HMG-CoA reductase inhibitor that is used to lower LDL cholesterol levels and to aid in the management of cardiovascular diseases. Animal studies have demonstrated that this drug has vasculoprotective properties.</p>

<p>γ-secretase inhibitor; reduces amyloid-β in brainÂ</p>

<p>Antirheumatic; immunosuppressant; neuroprotective; neuroregenerative</p>

<p>A specific inhibitor of Bone Morphogenetic Protein (BMP) type 1 receptors ALK2 and ALK3 (IC50  &lt; 0.5 µM). Dorsomorphin analog that exclusively targets the BMP but not VEGF signaling. It is able to inhibit the BMP-induced Smad1/5/8 activation but not the p38/MAP kinase signaling or Activin A-induced Smad2 activation.</p>

<p>Carmofur is an antineoplastic agent that is used to treat various cancers such as breast and colorectal cancer. This drug is a derivative of fluorouracil. Carmofur is an inhibitor of the human acid ceramidase, a lysosomal amidase involved in the development of cancer cells.</p>

<p>Sorafenib is a drug that belongs to the class of multikinase inhibitors. It inhibits a number of kinases, including the Mcl-1 protein, which is involved in apoptosis along with blocking picolinic acid (PA), an endogenous metabolite involved in apoptosis signal transduction. Sorafenib also binds to epidermal growth factor receptor (EGFR) on the surface of cancer cells, inhibiting the production of proteins that are required for angiogenesis, thus blocking the formation of new blood vessels. Sorafenib may also inhibit P-glycoprotein (Pgp) activity. Overall, these cytotoxic effects give Sorafenib anti-tumor properties, inhibiting angiogenesis and cellular transformation, which are the two main processes of tumor growth and metastasis. Sorafenib tosylate has been shown to be effective against a range of solid tumors such as breast, prostate and lung cancers and is also used for the treatment of metastatic colorectal cancer and renal cell carcinoma. A combination therapy group found that sorafenib was more effective when used with interferon alfa-2b for the treatment of advanced renal cell carcinoma. Sorafenib also has the potential for drug interactions with other drugs that are metabolized by cytochrome P450 enzymes.</p>

<p>Inhibitor of pan-class I PI3K family of lipid kinases; antineoplastic</p>

<p>SIRT1 activator</p>

<p>Inhibits interaction between small GTPase Rab27a and its effector JFC1 (synaptotagmin-like protein1, Slp1). These proteins regulate neutrophil exocytosis, decrease neutrophil infiltration in liver and kidneys and reduce extracellular ROS production by NAPDH oxidase. Thus, nexinhibib20 suppresses systemic inflammation.</p>

<p>Selective inhibitor of the platelet derived growth factor receptor PDGFRβ with IC50 value of 4.2 nM. JNJ 10198409 inhibits the PDGFRβ kinase activity and its downstream signalling leading to anti-proliferative and anti-angiogenic effects, which were confirmed in various tumoral cell lines.</p>

<p>Inhibitor of stearoyl-CoA desaturase SCD1 with IC50 of 6.3 nM, as measured in the SCD1-expressing human microsomes.  A 939572 exhibited anticancer activity as it reduced cell proliferation and triggered cell killing in human non-small cell lung carcinoma cells. A 939572 inhibited tumour growth in an in vivo model for gastric carcinoma and reduced the oleic acid:stearic acid ratio in mouse liver and plasma.</p>

<p>Inhibits mTORC1 and mTORC2 serine/threonine kinases</p>

<p>A 939572 is an inhibitor of stearoyl-CoA desaturase 1 (SCD1). It exhibits anticancer activity as it inhibits cell growth and promotes cell death in human non-small cell lung carcinoma cells.</p>