Enzyme Modulators

<p>Mirodenafil dihydrochloride is a potent phosphodiesterase-5 (PDE5) inhibitor, which is a synthetic compound with a primarily chemical origin. Its mode of action involves the inhibition of the enzyme PDE5, which predominantly resides in the smooth muscle cells lining blood vessels. By inhibiting PDE5, Mirodenafil dihydrochloride effectively increases the levels of cyclic guanosine monophosphate (cGMP), leading to the relaxation of smooth muscle tissues and vasodilation.</p>

<p>COX1 inhibitor; blocker of Ca2+-activated non-selective cation channels</p>

<p>Metformin is a widely used anti-hyperglycemic (anti-diabetic) agent for the treatment of type 2 diabetes mellitus. This is due to it decreasing blood glucose by decreasing hepatic glucose product by activation of the AMP-activated protein kinase AMPK. Studies have also demonstrated Metformin to have anti-cancer activity, attributed to several mechanisms such as inhibition of mammalian target of rapamycin (mTOR), cancer stem cells and inflammation.</p>

<p>Lenvatinib is an anti-cancer drug that is a multi-kinase inhibitor for VEGFR1, VEGFR2 and VEGFR. It has been shown to be effective against several cancers such as thyroid cancer and is currently in clinical trials for the treatment of leukaemia and prostate cancer. Furthermore, Lenvatinib also inhibits the activity of other protein kinases, including those involved in inflammatory responses.</p>

<p>Inhibitor of CSF1R receptor</p>

<p>Specific inhibitor of 8-oxoguanine glycosylase OGG1 with IC50 in submicromolar range. The compound inhibits binding of OGG1 to its substrate 8-oxoguanine, a guanine analog generated in the presence of reactive oxygen species (ROS). It was shown that TH5487 decreases inflammation level by inhibiting the base excision DNA repair in mice and altering the OGG1 chromatin dynamics. The compound also has implications in cancer biology since OGG1 inhibitors sensitise tumours to chemotherapy.</p>

<p>Inhibitor of HMG-CoA reductase</p>

<p>Gastric proton pump inhibitor</p>

<p>Neuronal selective nitric oxide synthase inhibitor</p>

<p>Farnesyl pyrophosphate synthase inhibitor; hepatic de novo lipogenesis inhibitor</p>

<p>Inhibitor of PIP5K1C</p>

<p>Irinotecan hydrochloride trihydrate is a topoisomerase I inhibitor that is used as chemotherapy drug for colorectal cancer. By inhibiting topoisomerase I, Irinotecan hydrochloride trihydrate prevents the replication of DNA in cells, and stops the cancer cells from growing and dividing. When used for chemotherapy, Irinotecan hydrochloride trihydrate is usually part of combination therapy with other chemotherapy drugs, such as 5-fluorouracil (5-FU) and leucovorin for other cancers.</p>

<p>Lenvatinib is a tyrosine kinase inhibitor that is used to treat cancers such as solid tumours. This drug inhibits the activity of VEGR receptors. It also inhibits other receptors such as fibroblast growth factor.</p>

<p>Tyrosine kinase inhibitor; antineoplastic activity; pro-apoptotic</p>

<p>Vorinostat is a histone deacetylase inhibitor which interferes with gene transcription regulatory mechanisms. It is used to treat cutaneous manifestations in patients with progressive, persistent, or recurrent cutaneous T- cell lymphoma (CTCL) following prior systemic therapies. This drug inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II).</p>

<p>Inhibitor of lipoprotein-associated phospholipase A2</p>

<p>Inhibitor of FLT3 receptor tyrosine kinases; anti-neoplastic</p>

<p>Glutamine analogue and antagonist of glutamine-dependent amidotransferases, with antibiotic and antifungal properties. Inhibits purine biosynthesis, FGAM synthetase and glucosamine-6-phosphate isomerase that contributes to its antineoplastic property. Azaserine can also act as a carcinogen, by inducing DNA carboxymethylation. Protects endothelial cells from inflammation under hyperglycemic conditions, via antioxidant mechanisms, independent of hexosamine biosynthetic pathway.</p>

<p>Inhibitor of O-GlcNAcase and N-acetylhexosaminidases</p>

<p>ATP competitive JAK2 inhibitor</p>

<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>

<p>The sequence of this peptide has been derived from a highly conserved region of the T-cell phosphatase TC.PTP45 and is an excellent general substrate for protein tyrosine phosphatases.The protein tyrosine phosphatase (PTP) superfamily has 103 enzymes that catalyse substrate dephosphorylation at tyrosine residues through a covalent enzyme intermediate involving a thiophosphate linkage from the active site cysteine residue. All PTPs share a common signature motif (I/V)HCXAGXGR(S/T), named the P-loop, responsible for the enzyme activity. The PTP superfamily can be divided into four classes based on their cellular localization/catalytic domains: the receptor-like PTPs (rPTPs), the non-receptor PTPs (nrPTPs), the low molecular weight PTP (LMWPTP), and the VH-1 and CDC-25 groups.PTPs are involved in regulating a plethora of cellular activities, including proliferation and differentiation, survival, migration, metabolism, and the immune response. Abnormal protein tyrosine phosphorylation has been associated with the etiology of various human diseases, including cancer, diabetes, and autoimmune dysfunctions, therefore making PTPs novel therapeutic targets.</p>

<p>Cyclin-dependent kinases (CDKs) are a family of kinases that regulate the cell cycle and gene transcription. Cyclin-dependent kinase 7 (CDK7) forms a trimeric complex with cyclin H and MAT1, which functions as a Cdk-activating kinase (CAK) and promotes cell cycle progression. CDK7 is an essential component of the transcription factor TFIIH, involved in DNA repair. CDK7 is also implicated in mRNA processing, transcription activation, pause induction, and pause release.CDK8 associates with the mediator complex and regulates transcription via several mechanisms, including influencing binding of RNA polymerase II to the mediator complex. CDK8 phosphorylates the Notch intracellular domain, SREBP, and STAT1. Its regulatory subunit is cyclin C. CDK9 is a component of the TAK/P-TEFb complex, which phosphorylates the part of RNA polymerase II. Its regulatory subunit is cyclin T or cyclin K. CDK9 interacts with HIV-1 Tat protein and TRAF2, and is involved in the differentiation of skeletal muscle.CDKs are often over expressed in cancers and may correlate with poor prognosis. This peptide is based on the C-terminal of RNA polymerase II and is used in kinase assays.</p>

<p>Ile-Pro-Pro (IPP) has the ability to inhibit angiotensin-converting enzyme and stimulate the production of nitric oxide. It could be used to improve hypertension thus reducing the risk of cardiovascular diseases.</p>

<p>Proprotein convertase subtilisin/kexin type 9 (PCSK9) is negative regulator of hepatic low-density lipoprotein (LDL) receptors by promoting their degradation. This leads to an increase in plasma levels of cholesterol-LDL (LDL-c). PCSK9 binds to the LDL receptor at the epidermal growth factor precursor homology domain A (EGF-A) which leads the receptor to be targeted for degradation. Natural loss of function mutations in PCSK9 have been linked to improved coronary health and lower cholesterol levels with reduced risk of coronary heart disease. This has led to further study to find inhibitors of PCSK9 with the hope that they may be clinically relevant in the future.As discussed, PCSK9 binds to EGF-A on the LDL receptor. A peptide named pep 2-8 is a mimic of EGF-A and binds PCSK9 in the same manner observed with the LDL receptor. Pep 2-8 is a potent selective competitive inhibitor of PCSK9. Pep 2-8 restores LDL receptor function and LDL uptake of PCSK9-treated HepG2 cells. This is still an active area of research to optimise inhibition of PCSK9 for cholesterol regulation.Pep 2-8 has also been utilised as an anchor peptide in phage-display experiments to bind an extension peptide library to the groove site.Peptide Ac-TVFTSWEEYLDWV-NH2 is a Research Peptide with significant interest within the field academic and medical research. This peptide is available for purchase at Cymit Quimica in multiple sizes and with a specification of your choice.</p>

<p>Abltide represents the optimal substrate peptide of Abl (or c-Abl), a non-receptor tyrosine kinase (NRTK) and the oncogenic Bcr-Abl tyrosine kinase (TK) (formed via a fusion between the Abelson (Abl) TK gene and the break point cluster region protein Brc). Abl was discovered as the gene from which the Abelson leukaemia virus derived its Gag-v-Abl oncogene.TKs are critical enzymes involved in multiple signalling pathways. However, Tks can promote cancer progression when deregulated, for example deregulated TK, Bcr-Abl gives rise to chronic myeloid leukaemia (CML) and Philadelphia chromosome-positive acute lymphocytic leukaemia (Ph+ ALL).Abl is activated by various signals including: growth factors, cytokines, cell adhesion, DNA damage and oxidative stress and results in the stimulation of both pro- and anti-apoptotic roles, cell proliferation or differentiation, retraction, or migration. Abl phosphorylates a large number of functionally diverse substrates, in part due to its ability to shuttle between the cytosol and the nucleus and bind both DNA and actin&amp;mdash-two biopolymers with fundamental roles in almost all biological processes.</p>

<p>H-FERQHM-OH peptide, corresponding to RNase A 8-13 (Chain A of bovine pancreatic ribonuclease) is a non-amyloidogenic peptide, that can be used as a negative control in amyloid formation experiments together with CRB1001320.</p>

<p>eV1-2 is a selective εPKC inhibitor peptide which interferes with protein-protein interactions between the ϵPKC isozyme and its anchoring protein (ϵRACK). ϵPKC and ϵRACK regulate the contraction rate of heart muscle cells and provide protection from ischemia induced cell death. ϵV1-2 is derived from the C2 domain of ϵPKC, a region important for protein-protein interactions and thus acts as a competitive inhibitor of these interactions. The C2 region is well conserved between species, but different enough from other PKC isozymes to allow for targeted inhibition (ϵV1-2 is 88% identical between sea slugs and rat ϵPKC, yet only 36% identical between rat ϵPKC and rat θ´PKC). This peptide contains a C-terminal cysteine residue for conjugation to a carrier protein.</p>

<p>Acid α-glucosidase (83-99) (human) is derived from the exogenous enzyme which degrades glycogen, maltose and isomaltose through targeting alpha -1,4 and alpha -1,6 linkages. Once synthesised in its precursor form, within the Golgi it is glycosylated and acquires mannose 6-phosphate residues. This allows it to be transported to the Lysosome in a multistep process.Pompe disease, also known as glycogen storage disease type II, can be diagnosed through the absence of acid α-glucosidase activity within patients. Therefore glycogen degradation in the lysosome is inhibited by this autosomal recessive disorder. This results in the accumulation of glycogen and tissue destruction, hence contributing to the pathologies of muscle weakness and respiratory failure, associated with infantile onset and adult onset Pompe disease.</p>

<p>ERKtide Substrate Peptide.</p>

<p>This peptide is phosphorylated by Janus kinase 2 (JAK2) and is an ideal substrate for use in kinase assays. The JAK family of kinases is essential for the signalling of a host of immune modulators in tumour, stromal, and immune cells where they are highly expressed. JAK family proteins mediate the signalling of the interferon (IFN), IL-6, and IL-2 families of cytokines.JAK kinases are associated with cytokine receptors. Cytokine binding to these receptors results in activation of JAK kinases and receptor phosphorylation. Phosphorylated cytokine receptors recruit STAT proteins, which are then phosphorylated by the activated JAK kinases. Phosphorylated STAT proteins form homo- and hetero-dimers that translocate into the nucleus and function as transcription factors.</p>