MAP3K Inhibitor

Takinib (EDHS-206) is an orally active and selective TAK1 inhibitor (IC₅₀=9.5 nM), more than 1.5 log more potent than the second and third ranked targets, IRAK4 (120 nM) and IRAK1 (390 nM), respectively. Takinib is an inhibitor of autophosphorylated TAK1 that non-competitively binds within the ATP binding pocket. Takinib induces apoptosis following TNFα stimulation in cell models of rheumatoid arthritis and metastatic breast cancer. Takinib is also a P. falciparum protein kinase 9 (PfPK9) inhibitor (K_D(app) of 0.46 μM).

5Z-7-Oxozeaenol is a natural anti-protozoan compound from fungal origin, acting as a potent irreversible and selective inhibitor of TAK1 and VEGF-R2, with IC₅₀s of 8 nM and 52 nM, respectively.

Selonsertib (GS-4997), an orally bioavailable, selective apoptosis signal-regulating kinase 1 (ASK1) inhibitor with a pIC₅₀ of 8.3, has been evaluated as an experimental treatment for diabetic nephropathy and kidney fibrosis.

CEP-14513 is an ALK inhibitor with an IC₅₀ of 4 nM. CEP-14513 also inhibits insulin receptor, VEGFR2, TIE2 and DLK kinases, but does not inhibit MET, IKKβ, or CDK1/2/5. CEP-14513 induces cancer cell apoptosis. CEP-14513 is applicable to research related to non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, and diffuse large B-cell lymphoma.

ZAK-IN-2 (Compound 8) is a selective, covalent ZAK inhibitor with an IC₅₀ of 11.5 nM. ZAK-IN-2 forms a covalent bond with Cys22 in the P-loop of ZAK to inhibit its kinase activity. ZAK-IN-2 inhibits the phosphorylation of the downstream target p38. ZAK-IN-2 blocks Doxorubicin (HY-15142A)-induced cleavage of Caspase 3. ZAK-IN-2 is applicable to research related to myocardial hypertrophy.

MAP3K14-IN-1 (Compound 173) is a MAP3K14 (NIK kinase) inhibitor with an IC₅₀ of 1.8 nM. MAP3K14-IN-1 inhibits the autophosphorylation of MAP3K14 kinase. MAP3K14-IN-1 reduces the level of phosphorylated IKKα in cancer cells. MAP3K14-IN-1 inhibits the proliferation of multiple myeloma cells. MAP3K14-IN-1 can be used in research related to multiple myeloma.

GNE-3511 is an orally active bioavailable and brain-penetrant dual leucine zipper kinase (DLK) inhibitor with a K_i of 0.5 nM. GNE-3511 can cross the blood-brain-barrier and can be used for the research of neurodegenerative diseases.

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

TAO Kinase inhibitor 1 (compound 43) is a selective, ATP-competitive thousand-and-one amino acid kinases (TAOK) inhibitor with IC₅₀s of 11 to 15 nM for TAOK1 and 2, respectively. TAO Kinase inhibitor 1 delays mitosis and induces mitotic cell death.

GLPG3312 (Compound 28) is an orally active SIK inhibitor with IC₅₀ values of 2.0 nM, 0.7 nM and 0.6 nM for SIK1, SIK2 and SIK3, respectively. GLPG3312 exhibits anti-inflammatory and immunomodulatory activity in vitro on human primary myeloid cells and in vivo in mouse models. GLPG3312 has good oral bioavailability and can be used for research on inflammatory and immune diseases.

SM1-71 (compound 5) is a potent TAK1 inhibitor, with a K_i of 160 nM, it also can covalently inhibit 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 inhibit proliferation of multiple cancer cell lines.

GS-444217 is a potent, orally available and selective ATP-competitive inhibitor of apoptosis signal-regulating kinase 1 (ASK1) with an IC₅₀ of 2.87 nM.

ZAK-IN-1 is an orally active and selective selective leucine-zipper and sterile‑α motif kinase (ZAK) inhibitor with IC₅₀ of 4 nM and K_D of 8 nM. ZAK-IN-1 exhibits excellent selectivity against a panel of 403 wild-type kinases. ZAK-IN-1 blocks p38/GATA-4 and JNK/c-Jun signaling and shows promising anti antihypertrophic cardiomyopathy (HCM) efficacy. ZAK-IN-1 can be used for the study of HCM.

Tpl2 Kinase Inhibitor 1 is a 3-pyridylmethylamino analog, and is a selective Tpl2 inhibitor (IC₅₀=50 nM). Tpl2 consists of COT kinase and MAP3K8. Tpl2 Kinase Inhibitor 1 plays an important role in the regulation of the inflammatory response and the progression of some cancers.

7,3',4'-Trihydroxyisoflavone, a major metabolite of Daidzein, is an ATP-competitive inhibitor of Cot (Tpl2/MAP3K8) and MKK4. 7,3',4'-Trihydroxyisoflavone has anticancer, anti-angiogenic, chemoprotective, and free radical scavenging activities.

GNE-8505 is an orally active, blood-brain barrier-permeable selective dual leucine zipper kinase (DLK) inhibitor. GNE-8505 has an IC₅₀ of 0.144 μM for pJNK, and EC₅₀ of 0.457 μM for DRG. GNE-8505 inhibits the DLK/JNK pathway, reduces stress-induced c-Jun phosphorylation levels, decreases neuronal death and suppresses axonal degeneration. GNE-8505 reduces phosphorylated c-Jun levels in the retina, spinal cord and brain tissues of mice. GNE-8505 is applicable to research related to Alzheimer's disease and amyotrophic lateral sclerosis (ALS).

Cot inhibitor-2 is a potent, selective and orally active cot (Tpl2/MAP3K8) inhibitor with an IC₅₀ of 1.6 nM. Cot inhibitor-2 inhibts TNF-α production in LPS-stimulated human whole blood with an IC₅₀ of 0.3 μM.

NQDI-1 inhibits apoptosis signal-regulating kinase 1 (ASK1) with a K_i of 500 nM and an IC₅₀ of 3 μM.

TAK1-IN-2 is a potent and selective TAK1 inhibitor, with an IC_50> of 2 nM.

TAK1/MAP4K2 inhibitor 1 is a potent dual TGFβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2) inhibitor, with IC₅₀s of 41.1 nM and 18.2 nM, respectively.