STAT Inhibitor

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).

Scutellarin, an active flavone isolated from Scutellaria baicalensis, can down-regulates the STAT3/Girdin/Akt signaling in HCC cells, and inhibits RANKL-mediated MAPK and NF-κB signaling pathway in osteoclasts. Scutellarin is active against HIV-1IIIB, HIV-1(74V) and HIV-1KM018 with EC₅₀s of 26 μM, 253 μM and 136 μM, respectively.

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].

Cryptotanshinone is a natural compound extracted from the root of Salvia miltiorrhiza Bunge that shows antitumor activities. Cryptotanshinone inhibits STAT3 with an IC₅₀ of 4.6 μM.

Napabucasin (BBI608) is a STAT3 inhibitor which blocks stem cell activity in cancer cells.

STAT5-IN-1 is a STAT5 inhibitor with an IC₅₀ of 47 μM for STAT5β isoform.

Pimozide is a dopamine receptor antagonist, with K_is of 1.4 nM, 2.5 nM and 588 nM for dopamine D2, D3 and D1 receptors, respectively, and also has affinity at α1-adrenoceptor, with a K_i of 39 nM; Pimozide also inhibits STAT3 and STAT5.

SD-36 is a potent STAT3 PROTAC degrader with a K_d of 44.4 nM and a K_i of 11 nM. SD-36 recruits the cereblon/culin 4A E3 ligase complex to mediate ubiquitination and proteasomal degradation of STAT3, inducing G1 phase cell cycle arrest and apoptosis. SD-36 is useful for research on acute myeloid leukemia, anaplastic large cell lymphoma, and hematopoietic and lymphoid malignancies.

Diosgenin, a steroidal saponin, can inhibit STAT3 signaling pathway. Diosgenin is an exogenous activator of Pdia3/ERp57. Diosgenin inhibits aortic atherosclerosis progression by suppressing macrophage miR-19b expression.

Sorafenib (Bay 43-9006) tosylate is a potent oral active multikinase inhibitor. Sorafenib blocks autophosphorylation and activity of receptor tyrosine kinases (VEGFR-2, VEGFR-3) and RAF family kinases, thereby suppressing the RAF/MEK/ERK and PI3K/Akt pathways, inhibiting STAT3 phosphorylation, and selectively inhibiting the MAPK pathway in cancer cells. Sorafenib tosylate induces cell cycle arrest, autophagy, apoptosis, and PARP cleavage, reduces Bcl-2, Bcl-XL, cyclin D1 levels, and activates Bak and Bax. Sorafenib tosylate inhibits tumor growth and metastasis in mouse and rat models. Sorafenib tosylate can be used for cancer research, such as colon, breast, non-small-cell lung cancer (NSCLC), ovarian, pancreatic, melanoma, colorectal and hepatocellular carcinoma.

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.

Liensinine is a bisbenzylisoquinoline alkaloid. By inhibiting the PI3K/AKT and JNK/p38-MAPK signaling pathways, Liensinine suppresses autophagy and apoptosis, clears Aβ, and exerts anti-inflammatory, antioxidant and neuroprotective effects. Liensinine activates AMPK and inhibits the expression of HIF-1α and VEGF, thereby suppressing angiogenesis. Liensinine exerts anti-tumor effects through ROS-mediated inhibition of the JAK2/STAT3 signaling pathway. Liensinine can be used for the research of diseases such as Alzheimer's disease, hepatocellular carcinoma, osteosarcoma, sepsis-induced organ injury and stroke.

AC-4-130 is a potent STAT5 SH2 domain inhibitor. AC-4-130 directly binds to STAT5 and disrupts STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent gene transcription. AC-4-130 induces cell cycle arrest and apoptosis in FLT3-ITD-driven leukemic cells. AC-4-130 has anti-cancer activity and can efficiently block pathological levels of STAT5 activity in acute myeloid leukemia (AML).

Saikosaponin D is a triterpene saponin isolated from Bupleurum, with anti-inflammatory, anti-bacterial, anti-tumor, and anti-allergic activities; Saikosaponin D inhibits selectin, STAT3 and NF-kB and activates estrogen receptor-β.

Pentadecylic acid is a saturated fatty acid with a 15-carbon backbone.

1-Stearoyl-sn-glycero-3-phosphocholine is a lysophosphatidylcholine that inhibits HDAC3 activity and phosphorylation of STAT3 in K562 cells. 1-Stearoyl-sn-glycero-3-phosphocholine induces apoptosis and exhibits anticancer activity in chronic myelogenous leukemia (CML) K562 cells.

Corylin is an orally active flavonoid anti-inflammatory and osteogenic agent that inhibits IL-6-induced STAT3 promoter activity and STAT3 phosphorylation. Corylin also has anticancer, antiatherosclerotic, and ameliorating activity in hyperlipidemia and insulin resistance, inducing adipocyte browning and lipolysis through SIRT1 or β3-AR-dependent pathways.

SC-43, a Sorafenib derivative, is a potent and orally active SHP-1 (PTPN6) agonist. SC-43 inhibits the phosphorylation of STAT3 and induces cell apoptosis. SC-43 has anti-fibrotic and anticancer effects.

STAT6-IN-3 is a phosphopeptide mimic targeting the SH2 domain of STAT6 and has a high affinity for STAT6 (IC₅₀: 0.04 μM). STAT6-IN-3 can be used in the research of inflammation such as asthma.

Sorafenib-d₃ (Donafenib) is the deuterated-labeled Sorafenib (HY-10201). Sorafenib (Bay 43-9006) is a potent oral active multikinase inhibitor. Sorafenib blocks autophosphorylation and activity of receptor tyrosine kinases (VEGFR-2, VEGFR-3) and RAF family kinases, thereby suppressing the RAF/MEK/ERK and PI3K/Akt pathways, inhibiting STAT3 phosphorylation, and selectively inhibiting the MAPK pathway in cancer cells. Sorafenib induces cell cycle arrest, autophagy, apoptosis, and PARP cleavage, reduces Bcl-2, Bcl-XL, cyclin D1 levels, and activates Bak and Bax. Sorafenib inhibits tumor growth and metastasis in mouse and rat models. Sorafenib can be used for cancer research, such as colon, breast, non-small-cell lung cancer (NSCLC), ovarian, pancreatic, melanoma, colorectal and hepatocellular carcinoma.