Enzyme Modulators

<p>Wee1 inhibitor with an IC50 of 5.2 nM</p>

<p>Inhibitor of TGF-α, CTGF, ERK1/2, NF-κB and FasL; anti-inflammatory</p>

<p>Inhibits non-receptor tyrosine kinase BTK; antineoplastic</p>

<p>Dual inhibitor of the adaptor protein 2-associated kinase 1 (AAK1) and BMP2-inducible kinase (BMP2K) with IC50 values of 270 nM and 1 μM, respectively. In a recent study, SGC AAK1 1 stabilised β-catenin, inhibited phosphorylation of the AP2 complex subunit mu protein (AP2M1) and activated Wnt signalling in in vitro experiments._x000D_</p>

<p>Potent and selective inhibitor of histone deacetylase 6 (HDAC6) with IC50 of 2.4 nM. Its anti-inflammatory activity was examined in a mouse model for acute colitis. The compound protected from intestinal inflammation by prevention of infiltration of CD19+ B-cells into the lamina propria of colonic epithelium and attenuated neutrophil activation. Its broad anti-inflammatory response involved decrease in 24 inflammatory chemokines and cytokines. Also, it is a potent inhibitor of cell proliferation in pancreatic cancer cell lines.</p>

<p>Hydroxychloroquine is a drug that is used to treat multiple types of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and discoid lupus. It is a prodrug, which is activated in the liver to hydroxychloroquine. It inhibits the production of inflammatory cytokines and nitric oxide by binding to the toll-like receptor 4 (TLR4) and inhibiting signaling pathways downstream of TLR4 activation. Additionally, Hydroxychloroquine is used to prevent and treat malaria caused by parasitic protozoan from the Plasmodium genus. Furthermore, recent studies revealed that hydroxychloroquine has beneficial effects on COVID-19 patients, as the current evidence shows that hydroxychloroquine inhibits SARS CoV-2 entry in host cells by interfering with endocytosis and affecting the glycoprofile on the spike glycoprotein.</p>

<p>Autophagy activator that acts through targeting the ATP6V1A subunit of vATPase</p>

<p>Short acting monoamine oxidase inhibitor</p>

<p>Cobicistat is an inhibitor of human cytochrome P450 3A enzymes (CYP) with no antiviral activity. Cobicistat is used in the treatment of HIV-1 infection, as an alternative to ritonavir, to increase the half-life of antiviral medications (von Hentig, 2016). Cobicistat acts as a booster by selectively inhibiting the hepatic degradation of the drugs, for example, in the pharmacological regime against HIV-1, which often includes protease inhibitors, such as, darunavir, atazanavir, and lopinavir, or the integrase inhibitor elvitegravir (Deeks, 2014).</p>

<p>Selective and potent inhibitor of 8-oxoguanine DNA glycosylase OGG1 with IC50 of 0.6 μM. OGG1 is a key enzyme in DNA repair mechanism called base excision repair (BER). The compound inhibits the hydrolysis of glycosidic bond required for the excision of 8-oxoguanine from double stranded DNA, which leads to accumulation of mutations. It has been proposed as monotherapy for certain types of cancers as well as adjuvant for cancer therapy with DNA damaging agents. It has potential to sensitize tumours for chemotherapy and inhibit development of drug resistance mechanisms.</p>

<p>Zileuton is an inhibitor of the 5-lipoxygenase enzyme, thus preventing the leukotrienes LTE4, LDT4, LTB4 and LTC4 from being formed. This in turn reduces inflammation, bronchoconstriction and mucus secretion in the airways. As a result, Zileuton can be used in the treatment and management of asthma and allergic rhinitis. Studies have shown that Zileuton has the potential to reverse dementia-related brain damage.</p>

<p>A cytidine analogue and inhibitor of DNA methyl transferases (DNMTs) with anti-cancer activity. This stable, hydrophilic compound forms covalent complexes between DNMT and zebularine-substrate DNA. It causes DNA lesions that block replication and cause replication fork collapse, leading to the formation of DNA double-strand breaks. It was also shown that zebularine-induced DNA methylation decrease in the IL-1β promoter region and disrupts molecular mechanisms of neuroinflammation. Moreover, this molecule down-regulates the DNA-methylation profile in the pluripotency genes’ promoters, which leads to improved development of somatic cell nuclear transfer (SCNT) embryos.</p>

<p>EGFR tyrosine kinase inhibitor; pro-apoptotic; antiproliferative in cancer cells</p>

<p>Apremilast is the commercial name of a phosphodiesterase-4 (PDE4) inhibitor developed to treat chronic inflammatory disorders. Similarly to thalidomide, the apremilast molecule carries a phthalimide ring, but it lacks however the glutarimide ring needed to bind to cereblon, specifically targeted by thalidomide. As a drug, apremilast is indicated for the treatment of psoriasis and psoriatic arthritis.</p>

<p>VEGFR tyrosine kinase inhibitor</p>

<p>Inhibitor of MEK1 and MEK2 kinases</p>

<p>Thymidylate synthase inhibitor</p>

<p>Reversible inhibitor of trypsin</p>

<p>Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) which is used to treat various types of pain and inflammation caused by arthritis. It is also a COX-2 inhibitor which reduces gastrointestinal effects of this drug. Inhibiting these enzymes, allow for a decrease in inflammatory symptoms.</p>

<p>Immune suppressant; prevents pro-inflammatory cytokine release</p>

<p>Inhibitor of 5-lipoxygenase activating protein_x000D_</p>

<p>Inhibits YAP/Tead transcriptional activity. Has anti-tumour effects on oesophageal adenocarcinoma with therapeutic potential in combination with 5-FU. Involved in ferroptosis, mediated by iron-dependent ROS.</p>

<p>Inhibitor of Rho-kinases</p>

<p>A selective inhibitor of MEK5 protein kinase with an IC50 value of 4.3 nM. Blocks transcriptional activation of myocyte-specific enhancer factor 2C (MEF2C). Inhibits phosphorylation of ERK5 protein kinase and thereby reverses inhibition of TNF signaling induced by fluid shear stress in endothelial cells. Induces apoptosis in FLT3-ITD cells.</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>

<p>Atorvastatin is an HMG-CoA reductase inhibitor which is used to lower lipid levels and to reduce the risk of cardiovascular disease. This drug belongs to the class of medicines called statins. It lowers abnormal levels of cholesterol and lipids to reduce the risk of cardiovascular disease by inhibiting the enzyme HMG-CoA.</p>

<p>Drotaverine is an antispasmodic drug that is used to alleviate gastrointestinal and genitourinary smooth muscle spasms. This drug works by inhibiting phosphodiesterase-4 and increasing levels of cAMP leading to smooth muscle relaxation.</p>

<p>Inhibitor of COX-2 and PDE4 enzymes; NSAID of coxib class</p>

<p>Antagonist of Wnt signalling pathway by inhibiting the activity of Porcn, a member of the membrane-bound O-acyltransferase (MBOAT) family. Porcn is required for the palmitoylation of Wnt, mediating its secretion and signalling. Inhibits self-renewal in embryonic stem cells, whilst promoting differentiation to epiblast stem cells.</p>

<p>Inhibitor of COX1 cyclooxygenase</p>

<p>Polmacoxib is a non-steroidal anti-inflammatory drug (NSAID), which is derived through synthetic chemical processes. It functions as a selective cyclooxygenase-2 (COX-2) inhibitor. By selectively inhibiting the COX-2 enzyme, polmacoxib reduces the conversion of arachidonic acid to prostaglandins that mediate inflammation and pain, while sparing the COX-1 enzyme that protects gastric mucosa and maintains platelet function.</p>

<p>Fibroblast growth factor receptor inhibitor</p>

<p>Thalidomide is a piperidinyl isoindole drug that is used to treat various cancers such as myeloma and erythema nodosum leprosum. This drug is immunosuppressive and has anti-angiogenic activity. Thalidomide’s mechanism of action is not fully understood however it is thought to block the activity of tumor necrosis factor-alpha (TNF-α).</p>

<p>A selective VHL inhibitor that stabilizes the hydroxylated form of HIF-α, resulting in upregulation of downstream target genes and proteins. Provides a tool for studying hypoxic signaling pathway.</p>

<p>A small molecule inhibitor with high selectivity for CDK8 over CDK19. Increases IL-10 production in stimulated human and murine macrophages and dendritic cells. Modulatory action on inflammatory responses has therapeutic potential.</p>

<p>Ibandronate is a bisphosphate used in the treatment of osteoporosis in postmenopausal women. This drug slows down the activity of osteoclasts resulting in a slower process of bone breakdown. This drug also inhibits farnesyl diphosphate and induces apoptosis of hematopoietic tumor cells.</p>

<p>Bestatin is a competitive protease inhibitor. It inhibits aminopeptidase N and is being studied for the use and treatment for acute myelocytic leukemia.</p>

<p>Benserazide is a drug that is used for the treatment of Parkinson’s disease and restless leg syndrome. This drug is a decarboxylase inhibitor and is usually used in combination with Levodopa.</p>

<p>Dutasteride is an androgenic compound and a 5α-reductase inhibitor that is used to treat benign prostatic hyperplasia (BPH) and male pattern baldness. Dutasteride reduces prostate volume and improves symptoms of BPH by inhibiting the enzyme 5α-reductase, which converts testosterone to dihydrotestosterone.</p>

<p>Diclofenac is a non-steroidal anti-inflammatory drug that is used to treat the signs and symptoms of arthritis and osteoarthritis. This drug inhibits COX-1 and COX-2 enzymes. As a result, it reduces pain and inflammation in joints. Diclofenac is usually used as a first line therapy for acute and chronic pain.</p>

<p>HMG-CoA reductase inhibitor</p>

<p>Vardenafil is a phosphodiesterase type 5 inhibitor that binds to intracellular targets and competitively inhibits cyclic guanosine monophosphate (cGMP) hydrolysis thus increasing cGMP levels. Vardenafil can be used for the research of erectile dysfunction, hepatitis and diabetes.</p>

<p>AKTide-2T is a 14-mer peptide which has the ability to bind to the substrate binding domain of Akt1 with a Ki of 12mM. AKt1 is part of the Akt kinase family which are serine/threonine kinase and it is ubiquitously expressed. AKt1 performs roles such as promoting endothelial neoplasms and through phosphorylating angiogenic substrates AKt1 plays a role in angiogenesis. AKT kinases as a whole perform functional roles in cell proliferation, cell growth, survival and intermediary metabolism.During peptide library screening, AKTide-2T was found to contain the optimal motif for successful binding to AKT. When phosphoamino acid analysis of AKTide-2T was carried out it was observed that although AKTide-2T contained two potential AKT phosphorylation sites: serine or threonine, AKT only phosphorylated the serine site. Furthermore it was found that AKTide-2T exhibits properties of being a competitive inhibitor for example it competitively inhibits histone H2B from being phosphorylated by AKT.</p>

<p>PAC 1 is a small-molecule apoptosis inducer, derived from synthetic sources, with a unique mode of action targeting the apoptotic pathways in cancer cells. PAC 1 functions by selectively activating procaspase-3, an inactive precursor of the caspase enzymes, which play a crucial role in the execution phase of cell apoptosis. By facilitating the conversion of procaspase-3 to its active form, PAC 1 enhances the apoptotic response in cancer cells, promoting cell death and offering potential therapeutic advantages.</p>

<p>Inhibitor of PDE4 enzyme; anti-inflammatory</p>

<p>A cell permeable inhibitor of oligosaccharyltransferase that interferes with the transfer of mature glycan precursors to recipient proteins. Causes reduced proliferation, G1 arrest and senescence in EGFR- and FGFR-dependent non-small-cell lung carcinoma (NSCLC) cells.</p>

<p>Proteosome inhibitor; antineoplastic</p>

<p>Pamidronic acid is a bisphosphate used in the treatment of Paget’s disease, osteolytic bone lesions and in the treatment of hypercalcemia of malignancy. This drug inhibits farnesyl diphosphate and induces apoptosis of hematopoietic tumor cells.</p>

<p>Inhibitor of EGFR transmembrane receptor</p>

<p>Inhibitor of cytochrome P450; inhibitor of prostaglandin synthesis</p>