MAP3Ks (Mitogen-activated protein kinase kinase kinases), the top components of MAPK cascades, modulate many biological processes, such as growth, development and various environmental stresses. Based on the sequence of their kinase catalytic domain, MAP3Ks are classified into three groups: the MEKK-like, ZIK-like and Raf-like families. Raf-like MAP3Ks constitute largest MAP3K subfamily. Raf-like MAP3Ks play roles in response to biotic and abiotic stresses.
MAP3Ks often bind to both MAP4Ks and MAP2Ks in the same pathway. For example, MEKK1 (MAP3K1) binds to both the MAP4K NIK and the MAP2K MKK4, while NSY-1 (MAP3K) binds to the MAP2K SEK-1. MAP3Ks activates MAP2Ks by phosphorylation of a serine and/or threonine, and MAP2Ks activate MAPKs by dual phosphorylation of a Thr-X-Tyr motif.
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NQDI-1 is a potent and selective inhibitor of apoptosis signal-regulating kinase 1 (ASK1) with Ki of 500 nM; inhibits in vivo expression levels of ASK1, phosphorylated (p‑)JNK, p‑c‑Jun, p53 and caspase 3 in Hypoxia-ischemia rat model; enhances endochondral bone formation by increasing chondrocyte survival in mice.
GNE-3511 is a potent, selective, orally bioavailable, brain-penetrant dual leucine zipper kinase (DLK, MAP3K12) inhibitor with Ki of <0.5 nM, displays >100-fold selectivity over MKK4/7, JNK1/2/3, MLK1/2/3; inhibits p-JNK with IC50 of 30 nM, displays concentration-dependent protection of neurons from degeneration in vitro (DRG IC50=107 nM) and demonstrates dose-dependent activity in multiple animal models of neurodegenerative disease.
MAP3K14 inhibitor 173 is a novel potent MAP3K14 kinase inhibitor with IC50 of 1.8 nM (NIK autophosphorylation); inhibits p-IKKα levels of L363 (NIK translocated multiple myeloma) cells with IC50 of 1.3 nM; exhibits antiproliferative activity on JJN-3 (NIK translocated) multiple myeloma cells (IC50=29 nM).
AKS1 inhibitor 19
AKS1 inhibitor 19 is a novel potent, selective and orally active ASK1 (MAP3K5) inhibitor with pIC50 of 8.3; displays good kinase selectivity with only 32 kinases having less than 30 fold selectivity in a panel of 356 kinases; inhibits phospho-JNK with pEC50 of 8.2 in cellular assays; displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury.
TCASK10 is a potent, highly specific inhibitor of ASK1 with IC50 of 14 nM, 30-fold selectivity over ASK2 (IC50=510 nM) and no activity against MEKK1, TAK1, IKKβ, ERK1, JNK1, p38α, GSK-3β, PKCθ and B-raf; blocks downstream JNK1/p38 phosphorylation in cells, dose-dependently reduces mitogen (FBS, PDGF and EGF)-induced airway smooth muscle (ASM) growth, also prevents TGFb1-induced migration of ASM cells in vitro.
GS-444217 (GS444217) is a potent, selective, ATP-competitive, orally available inhibitor of ASK1 with Kd/IC50 of 4.1/2.87 nM; displays >53-fold selectivity over DYRK1A and 104-fold over RSK4 in a panel of 442 kinases; strongly suppresses the activation of ASK1, p38, and JNK in the kidney resulting in decreased death of parenchymal cells, inflammation, and fibrosis;abrogates p38 MAPK activation in diabetic kidneys but has no effect upon hypertension in Nos3(-/-) mice; dose dependently reduced pulmonary arterial pressure and reduced RV hypertrophy in pulmonary arterial hypertension (PAH) models; also reduces the progressive inflammation and fibrosis in the kidney and halted decline of glomerular filtration rate in models of kidney disease, causes regression of fibrosis combined with RAS inhibitor enalapril.
A potent, selective Tpl2 (cot/MAP3K8) inhibitor with IC50 of 1.6 nM; dispalys 6875-fold selectivity over EGFR. P38, Src, CAMKII, MK2, PKA, and PKC (IC50>10 uM); inhibits LPS-induced TNF-α production in whole blood with IC50 of 0.3 uM; shows good efficacy in inhibiting TNF-alpha production in a LPS-stimulated rat inflammation model; orally active.
Selonsertib (GS-4997) is a highly selective and potent, ATP-competetive inhibitor of ASK1 (Apoptosis Signal-regulating Kinase 1, MAP3K5) with potential anti-inflammatory, antineoplastic and anti-fibrotic activities; orally bioavailable.
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