MAP4Ks (Mitogen-activated protein kinase kinase kinase kinases) belong to the mammalian Ste20-like family of serine/threonine kinases. MAP4K family members, including Hematopoietic progenitor kinase 1 (HPK1/MAP4K1), Germinal centre kinase (GCK/MAP4K2), Germinal centre kinase-like kinase (GLK/MAP4K3), HPK/GCK-like kinase (HGK/MAP4K4), Misshapen-like kinase 1 (MINK1/MAP4K6) and TRAF2 and NCK interacting kinase (TNIK/MAP4K7), as potent LATS1/2-activating kinases.
Overexpression or deletion of MAP4Ks affects the phosphorylation and activity of Large tumor suppressor 1/2 (LATS1/2, homologues of Wts) and Yes-associated protein (YAP) /transcriptional co-activator with PDZ-binding motif (TAZ). By acting in a LATS-dependent, but Mammalian Ste20-like kinases 1/2 (MST1/2, homologues of Hpo)-independent manner, MAP4Ks restrict the activity of YAP/TAZ by promoting their phosphorylation and inhibiting target gene expression. MAP4Ks are components of the Hippo pathway by directly phosphorylating and activating the LATS1/2 kinases.MAP4K2/4/6 and MST1/2 both belong to the STE20-like kinase family, and their kinase domains are highly homologous to one another. MAP4K4 acts through LATS to inhibit YAP and cell proliferation.
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A potent and highly selective, cell permeable MAP4K4 inhibitor with IC50 of 3.7 nM; exhibits adequate potency preventing migration of HUVEC cells in vitro (IC50=57 nM); has good PK and demonstrates in vivo efficacy in a retinal angiogenesis model .
DMX-5804 (DMX5804) is a potent, selective small-molecule inhibitor of MAP4K4 with IC50 of 3 nM; displays >100-fold selectivity over GCK/MAP4K2, GLK/MAP4K3, KHS/MAP4K5 and VEGFR; rescues cell survival, mitochondrial function, and calcium cycling in hiPSC-CMs (human induced-pluripotent-stem-cell-derived cardiomyocytes), protects hiPSC-CMs with EC50 of 500 nM for cell death induced by 400 uM H2O2; reduces infarct size and ischemia-reperfusion injury in mice in mice.
HG6-64-1 is a potent dual TAK1 and MAP4K2 ((germinal center kinase, GCK)) inhibitor with IC50 of 41 nM and 98 nM, respectively; also inhibits ZAK, p38α, Src, Lyn, CSK and EPH-family kinases (IC50=50-100 nM); inhibits GCK signaling DLBCL cell lines with EC50 of 1.83-157 nM, induces G0/G1 cell-cycle arrest and cell death; inhibits the growth of DLBCL xenograft tumors and prolongs the survival of tumor-bearing mice.
GNE-220 is a potent and selective inhibitor of MAP4K4 with IC50 of 7 nM, also inhibits MINK (MAP4K6), DMPK and KHS1 (MAP4K5) with IC50 of 9 nM, 476 nM and 1,110 nM; alters HUVEC sprout morphology, shifts the distribution of subcellular protrusion and increases total protrusions, dose-dependently increases the number of β1-integrin in long focal adhesions.
PF-06260933 (PF06260933,PF6260933) is a potent, selective, orally available MAP4K4 inhibitor with IC50 of 3.7 nM; demonstrates very good selectivity against more than 150 native kinases, with only the closely related GCK family members (ZC2, TNIK and ZC3, MINK 70% inhibition at 1 uM); inhibits LPS-induced plasma TNFα levels in mouse model.
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