tak1

TAK1 MAP4K2 inhibitor 1 is a potent dual inhibitor of TGFβ-activated kinase 1 (TAK1) and MAP4K2 [IC50s: 41.1 nM and 18.2 nM].

AZ-Tak1 is a potent and a relatively selective inhibitor of TAK1 kinase activity, with an IC50 of 0.009 mM. AZ-Tak1 treatment decreased the level of p38 and ERK in mantle cell lymphoma cells, and induced apoptosis in a dose and time dependent manner, with an IC50 of 0.1–0.5 mM. Using the annexin-V and PI staining and FACS analysis, After 48 hours of incubation, AZ-Tak1 (0.1 mM) induced apoptosis in 28%, 34% and 86% of Mino, SP53, and Jeko cells, respectively, which was increased to 32%, 42%, and 86% when 0.5 mM concentration was used.

TAK1-IN-3 is a novel ATP-competitive TAK1 inhibitor for the study of cancer.

TAK1 inhibitor is an inhibitor, which can inhibit MCF-7, A549, DU-145 and MDA MB-231, with IC50 of 0.021, 0.14, 0.064 and 0.19, respectively. TAK1 inhibitor showed good antibacterial activity with microphones ranging from 93.7 to 46.9μg/mL and from 7.8 to 5.8μg/mL.

TAK1-IN-2 is a potent and selective TAK1 inhibitor with an IC50 of greater than 2 nM [1].

(R)-STU104 is a novel TAK1-MKK3 protein-protein interaction (PPI) inhibitor that inhibits TNF-α and suppresses the TAK1/MKK3/p38/MnK1/MK2/elF4E signalling pathway by binding to MKK3 and disrupting TAK1 phosphorylation of MKK3. (R)-STU104 is a candidate compound for the treatment of ulcerative colitis.

TAK-715 is a p38 MAPK inhibitor for p38α.

Takinib (EDHS-206) is a specific and effective TAK1 inhibitor(IC50= 9.5 nM).

HM43239 is an orally active and selective FLT3 inhibitor with IC 50 s of 1.1 nM, 1.8 nM and 1.0 nM for FLT3 WT, FLT3 internal tandem duplication (ITD) and FLT3 D835Y kinases, respectively. HM43239 directly inhibits the kinase activity of FLT3 as a reversible Type I inhibitor and effectively modulates downstream p-STAT5 and p-ERK. HM43239 also demonstrated inhibition of SYK, JAK1 2 and TAK1. HM43239 inhibits the proliferation and induces the apoptosis of leukemic cells [1] [2] [3].

NG25 is a potent dual inhibitor of TAK1 and MAP4K2, with IC50s of 149 nM and 21.7 nM, respectively.

INH14 is a novel inhibitor of the IKKα β-dependent TLR inflammatory response (IC50s: 8.97 3.59 μM for IKKα IKKβ).

5Z-7-Oxozeaenol (FR148083) is a potent, irreversible and selective inhibitor of transforming growth factor (TGF)-β-activated kinase 1 with IC50 of 8.1 nM for TAK1 and low activity against MEK1 with IC50 of 411 nM, it is also an inhibitor of VEGF-R2 with IC50 of 52 nM.

HS220 is an inhibitor of TAK1 which plays a key role in the signaling pathways of inflammation and cell survival.

Torilin is an inhibitor of testosterone 5 alpha-reductase, it (IC50 = 31.7 + - 4.23 microM) shows a stronger inhibition of 5 alpha-reductase than alpha-linolenic acid (IC50 = 160.3 + - 24.62 microM) but is weaker than finasteride (IC50 = 0.38 + - 0.06 microM). Torilin has immunomodulatory, hepatoprotective, and anti-inflammatory properties, it inhibits inflammation by limiting TAK1-mediated MAP kinase and NF-κB activation, it can attenuate arthritis severity, modify leukocyte activations in dLNs or joints, and restore serum and splenocyte cytokine imbalances. Torilin inhibits melanin production in alpha-melanocyte stimulating hormone-activated B16 melanoma cells, with an IC(50) value of 25 microM. Torilin shows excellent antimicrobial activity against Bacillus subtilis ATCC 6633 spores and vegetative cells. Torilin has a potent anti-angiogenic activity both in vivo and in vitro, and it may have a strong activity to suppress tumorigenesis by inhibition of tumor invasion, it reverses multidrug-resistance in cancer cells, it can potentiate the cytotoxicities of adriamycin, vinblastine, taxol and colchicine against multidrug-resistant KB-V1 and MCF7 ADR cells.

Euscaphic acid has anti-diabetic, and anti-inflammatory activities, it inhibits LPS-induced inflammatory responses by interference with the clustering of TRAF6 with IRAK1 and TAK1, resulting in blocking the activation of IKK and MAPKs signal transduction

HS-276 is a highly selective, orally active inhibitor of TAK1 (Ki: 2.5 nM). HS-276 significantly inhibits TAK1 (IC50: 8.25 nM), CLK2 (IC50: 29 nM), GCK (IC50: 22 nM), ULK2 (IC50: 63 nM), MAP4K5 (IC50. HS-276 can be used to study rheumatoid arthritis (RA).

IRAK4-IN-21 is a selective, orally active, potent IRAK4 inhibitor that acts on IRAK4 (IC50: 5 nM) and TAK1 (IC50: 56 nM). IRAK4-IN-21 exhibits potent inhibition of IL-23 production with an IC50 value of 0.17 μM. can be used to study autoimmune diseases, such as plaque psoriasis and psoriatic arthritis.

(5E)-7-Oxozeaenol is a resorcylic acid lactone that has been found in the fungus MSX 63935 and has enzyme inhibitory and anticancer activities.1,2 It inhibits TGF-β-activated kinase 1 (TAK-1; IC50 = 1.3 μM).1 (5E)-7-Oxozeaenol inhibits proliferation of MCF-7, H460, SF-268, HT-29, and MDA-MB-435 human cancer cells with IC50 values of 4.9, 1.2, 5.6, 4.4, and 5.5 μM, respectively.2 |1. Fakhouri, L., El-Elimat, T., Hurst, D.P., et al. Isolation, semisynthesis, covalent docking and transforming growth factor beta-activated kinase 1 (TAK1)-inhibitory activities of (5Z)-7-oxozeaenol analogues. Bioorg. Med. Chem. 23(21), 6993-6999 (2015).|2. Ayers, S., Graf, T.N., Adcock, A.F., et al. Resorcylic acid lactones with cytotoxic and NF-κB inhibitory activities and their structure-activity relationships. J. Nat. Prod. 74(5), 1126-1131 (2011).

NG 25 is a type II kinase inhibitor that inhibits MAP4K2 and TAK1 (IC50s = 21.7 and 149 nM, respectively).1It also inhibits the Src family kinases Src and LYN (IC50s = 113 and 12.9 nM, respectively) and Abl family kinases (IC50s = 75.2 nM), as well as CSK, FER, and p38α (IC50s = 56.4, 82.3, and 102 nM, respectively). NG 25 (100 nM) prevents TNF-α-induced IKKα/β phosphorylation and IκB-α degradation in L929 cells. It inhibits secretion of IFN-α and IFN-β induced by CpG type B and CL097, respectively, in Gen2.2 cells in a concentration-dependent manner.2NG 25 decreases cell viability of HCT116KRASWT, and to a greater degree of HCT116KRASG13D, colorectal cancer cells in a concentration-dependent manner.3It also reduces tumor growth and increases the number of TUNEL-positive tumor cells in a CT26KRASG12Dmouse orthotopic model of colorectal cancer. 1.Tan, L., Nomanbhoy, T., Gurbani, D., et al.Discovery of type II inhibitors of TGFβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2)J. Med. Chem.58(1)183-196(2015) 2.Pauls, E., Shpiro, N., Peggie, M., et al.Essential role for IKKβ in production of type 1 interferons by plasmacytoid dendritic cellsJ. Biol. Chem. 287(23)19216-19228(2012) 3.Ma, Q., Gu, L., Liao, S., et al.NG25, a novel inhibitor of TAK1, suppresses KRAS-mutant colorectal cancer growth in vitro and in vivoApoptosis24(1-2)83-94(2019)

Antibiotic LL Z1640-2 is an inhibitor against the TAK1 activity.

IRAK4-IN-22 is a selective, orally active, potent IRAK4 inhibitor that acts on IRAK4 (IC50: 3 nM) and TAK1 (IC50: 17 nM). IRAK4-IN-21 exhibits potent inhibition of IL-23 production with an IC50 value of 0.10 μM. IRAK4-IN-21 can be used to study autoimmune diseases, such as plaque psoriasis and psoriatic arthritis.

KW 4099 is a thromboxane A2 antagonist.

NG25 trihydrochloride is a type II kinase inhibitor that inhibits MAP4K2 and TAK1. It also inhibits the Src family kinases Src and LYN and Abl family kinases as well as CSK, FER, and p38α. NG 25 prevents TNF-α-induced IKKα/β phosphorylation and IκB-α degradation in L929 cells. It inhibits secretion of IFN-α and IFN-β induced by CpG type B and CL097, respectively. NG 25 decreases cell viability of HCT116KRASWT, and to a greater degree of HCT116KRASG13D, colorectal cancer cells in a concentration-dependent manner. It also reduces tumor growth and increases the number of TUNEL-positive tumor cells in a CT26KRASG12D mouse orthotopic model of colorectal cancer.

Pelubiprofen is an orally active, non-steroidal anti-inflammatory agent, a selective cyclooxygenase-2 (COX-2) inhibitor, which effectively reduces PGE(2) production by inhibiting COX activity. Pelubiprofen inhibits LPS-induced phosphorylation of IKK-β and transforming growth factor-β activated kinase-1 (TAK1).

SM1-71 is a potent multi-targeted acrylamide-modified TAK1 inhibitor that inhibits MKNK2, MAP2K1 2 3 4 6 7, GAK, AAK1, BMP2K, MAP3K7, MAPKAPK5, GSK3A B, MAPK1 3, SRC, YES1, FGFR1, ZAK (MLTK), MAP3K1, LIMK1 and RSK2.SM1-71 can be used as a kinase probe with anticancer activity and inhibits the proliferation of various cancer cell lines.

RGB-286638 free base is a novel CDK inhibitor with IC50s of 1 nM/2 nM/3 nM/4 nM/5 nM for cyclin T1-CDK9/cyclin B1-CDK1/cyclin E-CDK2/cyclin D1-CDK4/cyclin E-CDK3/p35-CDK5 respectively; less potent against cyclin H-CDK7 and cyclin D3-CDK6.

1,3,5-Trihydroxy-4-prenylxanthone is a relatively potent inhibitor of phosphodiesterase type 5 (PDE5) with an IC50 of 3.0 μM; it exhibits in vitro inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values of 56.3plusmn;0.4 and 46.0plusmn;0.3 M, respectively. It also inhibits LPS-induced NF-κB and AP-1 activations by interfering with the posttranslational modification (phosphorylation and or ubiquitinylation) of IRAK-1, disrupting TAK1-mediated activation of IKK and MAPKs signal transduction.

cRIPGBM chloride is an orally active, proapoptotic compound derived from glioblastoma multiforme (GBM) cancer stem cells (CSCs). It specifically targets receptor-interacting protein kinase 2 (RIPK2) to trigger caspase 1-dependent apoptosis. By inhibiting the formation of the RIPK2/TAK1 prosurvival complex and promoting the assembly of the RIPK2/caspase 1 proapoptotic complex, cRIPGBM chloride efficiently suppresses tumor growth. This action results in significant anti-tumor activity in animal models in vivo.

RGB-286638 is a multi-target CDK inhibitor that effectively hampers the kinase activity of a range of cyclin-CDK complexes, including cyclin T1-CDK9 (IC50 = 1 nM), cyclin B1-CDK1 (IC50 = 2 nM), cyclin E-CDK2 (IC50 = 3 nM), cyclin D1-CDK4 (IC50 = 4 nM), cyclin E-CDK3 (IC50 = 5 nM), and p35-CDK5 (IC50 = 5 nM). Additionally, it inhibits other kinases such as GSK-3β (IC50 = 3 nM), TAK1 (IC50 = 5 nM), Jak2 (IC50 = 50 nM), and MEK1 (IC50 = 54 nM), showcasing its versatile inhibitory potential.

PF-05381941 is a potent dual inhibitor of TAK1 p38α, exhibiting IC50 values of 156 nM and 186 nM, respectively[1].

CBP501 is a peptide with G2 checkpoint-abrogating activity. G2 checkpoint inhibitor CBP501 inhibits multiple serine/threonine kinases, including MAPKAP-K2, C-Tak1, and CHK1, that phosphorylate serine 216 of the dual-specific phosphatase Cdc25C (cell division checkpoint 25 C); disruption of Cdc25C activity results in the inhibition of Cdc25C dephosphorylation of the mitotic cyclin-dependent kinase complex Cdc2/cyclin B, preventing entry into the mitotic phase of the cell cycle.

2-Methoxystypandrone displays an immunomodulatory effect in a cellular model, it blocks inflammatory responses by impairing NF-κB signaling to limit the inflammation and oxidative stress for preservation of BBB integrity. 2-Methoxystypandrone concomitant