JAK Inhibitor

Ruxolitinib (INCB18424) is an orally active and selective JAK1/2 inhibitor with IC₅₀s of 3.3 nM and 2.8 nM in cell-free assays, and has 130-fold selectivity for JAK1/2 over JAK3. Ruxolitinib induces autophagy and kills tumor cells through toxic mitophagy.

Tofacitinib is an orally available JAK3/2/1 inhibitor with IC₅₀s of 1, 20, and 112 nM, respectively.

Upadacitinib (ABT-494) is a potent, orally active and selective Janus kinase 1 (JAK1) inhibitor (IC₅₀=43 nM). Upadacitinib (ABT-494) displays approximately 74 fold selective for JAK1 over JAK2 (200 nM) in cellular assays dependent on specific, relevant cytokines. Upadacitinib (ABT-494) can be used for several autoimmune disorders research.

Baricitinib (LY3009104; INCB028050) is a selective and orally bioavailable JAK1 and JAK2 inhibitor with IC₅₀s of 5.9 nM and 5.7 nM, respectively.

Deucravacitinib (BMS-986165) is an orally active allosteric inhibitor of tyrosine kinase 2 (TYK2), with an IC₅₀ of 0.2 nM and a K_i of 0.02 nM against the JH2 domain of TYK2, and it exhibits selectivity over other JAK subtypes and most of the kinome. Deucravacitinib blocks IL-23, IL-12, p-STAT1/3 and Type I IFN signaling, and inhibits Th17/Th1-mediated psoriasis inflammation. Deucravacitinib can be used in research related to moderate-to-severe plaque psoriasis, inflammatory bowel disease and systemic lupus erythematosus.

Fadeucravacitinib (Tyk2-IN-8) is an orally active selective TYK2 inhibitor with an IC₅₀ of 5.7 nM against the JH2 pseudokinase domain. Fadeucravacitinib specifically binds to the TYK2 JH2 domain to exert allosteric inhibition, reduces JH1 kinase activity, and thereby blocks the TYK2/STAT pathway and pro-inflammatory signaling cascades. Fadeucravacitinib can be used in research related to inflammatory bowel disease.

Fedratinib (TG-101348) is a potent, selective, ATP-competitive and orally active JAK2 inhibitor with IC₅₀s of 3 nM for both JAK2 and JAK2V617F kinase. Fedratinib shows 35- and 334-fold selectivity over JAK1 and JAK3, respectively. Fedratinib induces cancer cell apoptosis and has the potential for myeloproliferative disorders research.

AG490 (Tyrphostin AG490) is a tyrosine kinase inhibitor that inhibits EGFR, Stat-3 and JAK2/3.

Ruxolitinib phosphate (INCB018424 phosphate) is a potent JAK1/2 inhibitor with IC₅₀s of 3.3 nM/2.8 nM, respectively, showing more than 130-fold selectivity over JAK3.

Pentagalloylglucose (Penta-O-galloyl-β-D-glucose) is an orally active gallic tannin compound and an inducer of apoptosis and autophagy. Pentagalloglucose induces cell apoptosis and autophagy through the GSK3β/β-catenin pathway. Pentagalloylglucose inhibits UBE2T-mediated p53 ubiquitination, upregulates p53, downregulates RRM1/RRM2 in pancreatic cancer organoids. Pentagalloglucose has antioxidant, anti mutagenic, anti-inflammatory, anticonvulsant, cardioprotective, anti allergic, cholesterol lowering, and anti-tumor activities.

Tofacitinib citrate is an orally available JAK3/2/1 inhibitor with IC₅₀s of 1, 20, and 112 nM, respectively. Tofacitinib citrate has antibacterial, antifungal and antiviral activities.

Ritlecitinib (PF-06651600) is a highly selective, orally active, irreversible covalent JAK3 inhibitor (IC₅₀=33 nM) without inhibitory activity towards JAK1, JAK2, and TYK2 (IC₅₀ >10 μ M). Ritlecitinib rapidly inactivates the JAK3 kinase, and blocks signaling and downstream STAT phosphorylation mediated by common gamma chain cytokines such as IL-2 and IL-15. Ritlecitinib can inhibit Th1/Th17 cell differentiation and function, and effectively suppress preclinical animal models such as alopecia areata, adjuvant-induced arthritis (AIA), and experimental autoimmune encephalomyelitis (EAE).

Pacritinib (SB1518) is a potent inhibitor of both wild-type JAK2 (IC₅₀=23 nM) and JAK2^V617F mutant (IC₅₀=19 nM). Pacritinib also inhibits FLT3 (IC₅₀=22 nM) and its mutant FLT3^D835Y (IC₅₀=6 nM).

WP1066 is an inhibitor of JAK2 and STAT3, and also shows effect on STAT5 and ERK1/2, without affecting JAK1 and JAK3. WP1066 can cross the blood-brain barrier[1][2][3][4].

Momelotinib (CYT387) is an ATP-competitive inhibitor of JAK1/JAK2 with IC₅₀a of 11 nM and 18 nM,respectively. CYT387 shows much less activity against JAK3.

Gamma-glutamylcysteine (γ-Glu-Cys) is an orally active, blood-brain barrier permeable dipeptide. Gamma-glutamylcysteine activates AMPK, SIRT1, IL-4/STAT6, AC/cAMP/PI3K, IGF-1R/IRS1/PI3K, and Nrf2 signaling pathways; it inhibits NF-κB, JAK1/STAT1/3, MAPKs, cadmium-induced p38 MAPK, JNK, and PI3K/Akt signaling pathways. Gamma-glutamylcysteine regulates macrophage polarization, modulates the trafficking of CD36 and GLUT4, induces glutathione synthesis, improves metabolic dysfunction, reduces lipid deposition, ameliorates glucose homeostasis, inhibits apoptosis (Apoptosis), stabilizes mitochondria, suppresses lipid peroxidation, iron accumulation and ferroptosis (Ferroptosis), reduces ds-HMGB1 levels, reverses mechanical hyperalgesia, and alleviates hepatic lipid droplet formation. Gamma-glutamylcysteine is applicable to research related to inflammatory bowel disease, type 2 diabetes, cadmium-induced neurotoxicity, Alzheimer's disease, cerebral ischemia/reperfusion injury, neuropathy, and alcoholic liver disease.

Abrocitinib (PF-04965842) is a potent, orally active and selective JAK1 inhibitor, with IC₅₀s of 29 and 803 nM for JAK1 and JAK2, respectively. Abrocitinib (PF-04965842) exhibits less active effect on TYK2 (IC₅₀, 1.253 μM), and inhibits phosphorylation of STAT1, STAT3 and STAT5 after stimulation. Effective in autoimmune disease.

Filgotinib (GLPG0634) is a selective, orally available JAK1 inhibitor with anti-inflammatory and antiviral activities. Filgotinib can effectively inhibit the activities of JAK1, JAK2, JAK3 and TYK2 with IC₅₀ values of 10 nM, 28 nM, 810 nM and 116 nM, respectively. Filgotinib also inhibits HIV-1 driven gene transcription and reduces proliferation of HIV-1 infected cells. Filgotinib can be used in the study of rheumatoid arthritis and inflammatory bowel disease.

Crocin (Crocin I) is an orally active natural product that can be isolated from the stigma of Crocus sativus. Crocin inhibits tumor cell proliferation and promotes apoptosis through JAK pathway. Crocin has anti-inflammatory, antioxidant and antitumor activities .

Itacitinib (INCB039110) is an orally active selective inhibitor of JAK1 with an IC₅₀ value of 2 nM for human JAK1. Itacitinib inhibits IFN-γ-mediated phosphorylation of STAT1 and downstream pro-inflammatory signaling pathways. Itacitinib reduces the frequency and number of splenic neutrophils in mouse models, downregulates the levels of pro-inflammatory cytokines and chemokines, and inhibits pro-inflammatory gene expression pathways. Itacitinib improves survival rate and clinical scores in mouse models of hemophagocytic lymphohistiocytosis (HLH), and also suppresses metastasis in NSCLC models with high Rab1A expression. Itacitinib can be used for research on hemophagocytic lymphohistiocytosis and non-small cell lung cancer.