Baricitinib is a selective and reversible inhibitor of Janus kinase (JAK)1 and JAK2. Janus kinases (JAKs) are enzymes that transduce intracellular signals from cell surface receptors for a number of cytokines and growth factors involved in haematopoiesis, inflammation and immune function. Within the intracellular signalling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), which activate gene expression within the cell. Baricitinib modulates these signalling pathways by partially inhibiting JAK1 and JAK2 enzymatic activity, thereby reducing the phosphorylation and activation of STATs. FDA issued an Emergency use authorization (EUA) on November 19, 2020 that permits use of baricitinib in combination with remdesivir for treatment of suspected or laboratory-confirmed COVID-19 in hospitalized patients ≥2 years of age requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).
Delgocitinib, a janus kinase (JAK) inhibitor, is being approved for the treatment of inflammatory skin conditions. Delgocitinib inhibited the activation of inflammatory cells, such as T cells, B cells, monocytes and mast cells, in vitro and inhibited Th1-, Th2- and Th17-type cytokine production from both T cells and non-T cells.
Fedratinib is an oral kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Fedratinib is a JAK2-selective inhibitor with higher inhibitory activity for JAK2 over family members JAK1, JAK3 and TYK2. Abnormal activation of JAK2 is associated with myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera.
Pacritinib is a kinase inhibitor with activity against Janus-associated kinase 2 (JAK2) and Fms-like receptor tyrosine kinase 3 (FLT3). Pacritinib inhibits both wild-type JAK2 and the JAK2V617F mutant form that is common in patients with myeloproliferative neoplasms. Pacritinib also exhibits inhibitory activity against additional cellular kinases (such as colony-stimulating factor 1 and interleukin 1 receptor-associated kinase 1), the clinical relevance of which is unknown.
Peficitinib inhibits the signal transduction of cytokines important for the pathological condition of RA as it inhibits the kinase activity of the JAK family (JAK1, JAK2, JAK3, and TYK2) and their signal transduction mediated by IL-2.
a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. Although some small studies have suggested possibility of benefit from ruxolitinib in patients with COVID-19, it is not recommended the use of JAK inhibitors other than baricitinib for the treatment of COVID-19.
Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.
Upadacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Upadacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.
Abrocitinib is a Janus kinase (JAK)1 inhibitor. JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Inhibition of JAK1 modulates the signalling pathways by preventing the phosphorylation and activation of STATs. It is used for treating adults with moderate to severe atopic dermatitis (also known as eczema, when the skin is itchy, red and dry).
An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter.
A benzamide and indazole derivative that acts as a TYROSINE KINASE inhibitor of the VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR. It is used in the treatment of advanced RENAL CELL CARCINOMA.
Ceritinib is a kinase inhibitor. Targets of ceritinib inhibition identified in either biochemical or cellular assays at clinically relevant concentrations include ALK, insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1. Among these, ceritinib is most active against ALK. Ceritinib inhibited autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells in in vitro and in vivo assays.
Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met.
Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. Dabrafenib also inhibits wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM, respectively, and other kinases such as SIK1, NEK11, and LIMK1 at higher concentrations. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Dabrafenib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo.
A pyrimidine and thiazole derived ANTINEOPLASTIC AGENT and PROTEIN KINASE INHIBITOR of BCR-ABL KINASE. It is used in the treatment of patients with CHRONIC MYELOID LEUKEMIA who are resistant or intolerant to IMATINIB.
Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2, and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK).
A quinazoline derivative and ANTINEOPLASTIC AGENT that functions as a PROTEIN KINASE INHIBITOR for EGFR associated tyrosine kinase. It is used in the treatment of NON-SMALL CELL LUNG CANCER.
Filgotinib is an adenosine triphosphate (ATP)-competitive and reversible inhibitor of the JAK family. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane. JAK1 is important in mediating inflammatory cytokine signals, JAK2 in mediating myelopoiesis and erythropoiesis and JAK3 plays critical roles in immune homeostasis and lymphopoiesis. Within the signalling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs) which modulate intracellular activity including gene expression. Filgotinib modulates these signalling pathways by preventing the phosphorylation and activation of STATs.
Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptor. The fostamatinib metabolite R406 reduces antibody-mediated destruction of platelets.
A tyrosine kinase inhibitor and ANTINEOPLASTIC AGENT that inhibits the BCR-ABL kinase created by chromosome rearrangements in CHRONIC MYELOID LEUKEMIA and ACUTE LYMPHOBLASTIC LEUKEMIA, as well as PDG-derived tyrosine kinases that are overexpressed in gastrointestinal stromal tumors.
Infigratinib is a small molecule kinase inhibitor of FGFR with IC50 values of 1.1, 1, 2, and 61 nM for FGFR1, FGFR2, FGFR3, and FGFR4, respectively. The major human metabolites of infigratinib, BHS697 and CQM157, have similar in vitro binding affinities for FGFR1, FGFR2, and FGFR3 compared to infigratinib. Infigratinib inhibited FGFR signaling and decreased cell proliferation in cancer cell lines with activating FGFR amplifications, mutations, or fusions. Constitutive FGFR signaling can support the proliferation and survival of malignant cells. Infigratinib had anti-tumor activity in mouse and rat xenograft models of human tumors with activating FGFR2 or FGFR3 alterations, including two patient-derived xenograft models of cholangiocarcinoma that expressed FGFR2-TTC28 or FGFR2-TRA2B fusions. Infigratinib demonstrated brain-to-plasma concentration ratios (based on AUC0-inf) of 0.682 in rats after a single oral dose.
Lorlatinib is a kinase inhibitor with in vitro activity against ALK and ROS1 as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors.
Midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases. In vitro biochemical or cellular assays have shown that midostaurin or its major human active metabolites CGP62221 and CGP52421 inhibit the activity of wild type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFR-alfa/beta, VEGFR2, as well as members of the serine/threonine kinase PKC (protein kinase C) family. Midostaurin demonstrated the ability to inhibit FLT3 receptor signaling and cell proliferation, and it induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors. Midostaurin also demonstrated the ability to inhibit KIT signaling, cell proliferation and histamine release and induce apoptosis in mast cells.
An antihelmintic that is active against most tapeworms. (From Martindale, The Extra Pharmacopoeia, 30th ed, p48). Although suggested as a potential treatment for COVID-19 based on its broad antiviral activity, including in vitro activity against coronaviruses, there are no data to support the use of niclosamide in the treatment of COVID-19.
Nilotinib is an inhibitor of the BCR-ABL kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of ABL protein. In vitro, nilotinib inhibited BCR-ABL mediated proliferation of murine leukemic cell lines and human cell lines derived from patients with Ph+ CML. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from BCR-ABL kinase mutations, in 32 out of 33 mutations tested. In vivo, nilotinib reduced the tumor size in a murine BCR-ABL xenograft model.
Pazopanib is a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-α and -β, fibroblast growth factor receptor (FGFR)-1 and -3, cytokine receptor (Kit), interleukin-2 receptor-inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). In vitro, pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-β receptors. In vivo, pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in a mouse model, and the growth of some human tumor xenografts in mice.
Pralsetinib is a kinase inhibitor of wild-type RET and oncogenic RET fusions (CCDC6-RET) and mutations (RET V804L, RET V804M and RET M918T) with half maximal inhibitory concentrations (IC50s) less than 0.5 nM. In purified enzyme assays, pralsetinib inhibited DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRb, and FGFR1 at higher concentrations that were still clinically achievable at Cmax. In cellular assays, pralsetinib inhibited RET at approximately 14-, 40-, and 12-fold lower concentrations than VEGFR2, FGFR2, and JAK2, respectively.
An indole and pyrrole derivative that inhibits VEGFR-2 and PDGFR BETA RECEPTOR TYROSINE KINASES. It is used as an antineoplastic agent for the treatment of GASTROINTESTINAL STROMAL TUMORS, and for treatment of advanced or metastatic RENAL CELL CARCINOMA.