MAP4K4/HGK

MAP4K4/HGK is a human STE20-related serine/threonine kinase that specifically activates the c-Jun N-terminal kinase (JNK) pathway^[1]. Mechanistically, the related Nck-interacting kinase (NIK) form binds NCK and MEKK1 and activates the SAPK/JNK cascade through a conserved regulatory domain^[2]. Therefore, MAP4K4/HGK provides a kinase node connecting adaptor proteins, MAPK signaling, and stress-responsive transcriptional programs^[1]^[2]. In endothelial models, MAP4K4 regulates integrin-FERM binding and controls endothelial cell motility, linking this kinase to adhesion remodeling and vascular migration assays^[3]. In tumor-cell screening, MAP4K4 was identified as a promigratory kinase, supporting its use in invasion, migration, and metastasis-related experimental designs^[4]. In inflammatory and metabolic models, TNF-α stimulates Map4k4 expression through TNFR1, c-Jun, and ATF2 signaling, and MAP4K4 gene silencing in human skeletal muscle prevents TNF-α-induced insulin resistance^[5]^[6]. In immune-metabolic disease models, HGK/MAP4K4 deficiency stabilizes TRAF2, promotes Th17 differentiation, and leads to insulin resistance^[7]. Compared with related MAP4K4 isoforms, colorectal cancer studies show that the RBM4-SRSF3-MAP4K4 splicing cascade modulates metastatic signatures, and MAP4K4 isoform levels correlate with migration and invasion^[8]. For experimental applications, GNE-495 is a potent and selective MAP4K4 inhibitor with efficacy in retinal angiogenesis, and it impedes pancreatic cancer growth and migration in disease models^[9]^[10].

References:

[1]. Yao Z, et al. A novel human STE20-related protein kinase, HGK, that specifically activates the c-Jun N-terminal kinase signaling pathway. J Biol Chem. 1999 Jan 22;274(4):2118-25. [Content Brief]

[2]. Su YC, et al. NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain. EMBO J. 1997 Mar 17;16(6):1279-90.

[3]. Vitorino P, et al. MAP4K4 regulates integrin-FERM binding to control endothelial cell motility. Nature. 2015 Mar 26;519(7544):425-30. [Content Brief]

[4]. Collins CS, et al. A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3775-80.

[5]. Tesz GJ, et al. Tumor necrosis factor alpha (TNFalpha) stimulates Map4k4 expression through TNFalpha receptor 1 signaling to c-Jun and activating transcription factor 2. J Biol Chem. 2007 Jul 6;282(27):19302-12.

[6]. Chuang HC, et al. HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance. Nat Commun. 2014 Aug 6;5:4602.

[7]. Lin JC, et al. RBM4-SRSF3-MAP4K4 splicing cascade modulates the metastatic signature of colorectal cancer cell. Biochim Biophys Acta Mol Cell Res. 2018 Feb;1865(2):259-272.

[8]. Ndubaku CO, et al. Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis. ACS Med Chem Lett. 2015 Jun 29;6(8):913-8. [Content Brief]

[9]. Singh SK, et al. MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3. Oncogene. 2021 Oct;40(43):6153-6165.

MAP4K4/HGK Inhibitors (17)

MAP4K4/HGK Related Products (17):

By Type:	Pan (7) Selective (7)

Cat. No.	Product Name	Effect	Purity

HY-160623

Rentosertib	Inhibitor	99.96%
Rentosertib (INS018 055) (compound 112) is the orally active TNIK and MAP4K4 inhibitor with IC₅₀ values of 12-120, 12-120 nM, respectively.

HY-100343

GNE-495	Inhibitor	99.49%
GNE-495 is a potent and selective MAP4K4 inhibitor with an IC₅₀ of 3.7 nM.

HY-19562

PF-06260933	Inhibitor	99.39%
PF-06260933 is an orally active and highly selective inhibitor of MAP4K4 with IC₅₀s of 3.7 and 160 nM for kinase and cell, respectively.

HY-111754

DMX-5804	Inhibitor	99.83%
DMX-5804 is a potent, orally active and selective MAP4K4 inhibitor, with an IC₅₀ of 3 nM, a pIC₅₀ of 8.55 for human MAP4K4, less potent on MINK1/MAP4K6 (pIC₅₀, 8.18), and TNIK/MAP4K7 (pIC₅₀, 7.96). DMX-5804 enhances cardiomyocyte survival, and reduces ischemia-reperfusion injury in mice.

HY-168972

Famlasertib	Inhibitor	99.94%
Famlasertib is a potent, brain-penetrant MAP4K inhibitor with IC₅₀s value of 0.3 nM, 23.7 nM, and 44.7 nM for HGK (MAP4K4), MLK3, and MLK1, respectively. Famlasertib shows motor neuron protection and anti-inflammatory properties. Famlasertib can be used for the study of amyotrophic lateral sclerosis (ALS).

HY-W207224

F1386-0303	Inhibitor
F1386-0303 is a highly selective MAP4K4 inhibitor with an IC₅₀ of 34 nM against human targets. F1386-0303 exerts cardiomyocyte protective and function-preserving effects through mechanisms such as alleviating oxidative stress, inhibiting caspases, and maintaining mitochondrial membrane potential, while it does not interfere with the activity of Doxorubicin (HY-15142A) in cancer cells. F1386-0303 is rapidly cleared and has no bioavailability in mice, but it is well-suited as a tool compound for target validation. F1386-0303 can be applied to studies related to cardiac ischemia-reperfusion injury, Doxorubicin-induced cardiotoxicity, myocardial infarction and other related conditions.

HY-125012

MAP4K4-IN-3	Inhibitor	99.77%
MAP4K4-IN-3 (Compound 17) is a potent and selective MAP4K4 inhibitor with an IC₅₀ of 14.9 nM in kinase assay, an IC₅₀ of 470 nM in cell assay. Antidiabetic agent.

HY-U00428A

GNE 220 hydrochloride	Inhibitor	98.22%
GNE 220 (hydrochloride) is a potent and selective inhibitor of MAP4K4, with an IC₅₀ of 7 nM.

HY-W003471

Pyrrolo[2,1-f][1,2,4]triazin-4-amine	Inhibitor
Pyrrolo[2,1-f][1,2,4]triazin-4-amine is a MAP4K4 inhibitor with a surface plasmon resonance (SPR) K_d of 88 μM and a ligand efficiency of 0.56.

HY-U00428

GNE 220	Inhibitor
GNE-220 is a potent and selective inhibitor of MAP4K4 with an IC₅₀ of 7 nM.

HY-W402208

MAP4K4-IN-7	Inhibitor
MAP4K4-IN-7 (Compound 8) is a MAP4K4 inhibitor. MAP4K4-IN-7 shows moderate inhibitory activity against TNIK, MAP4K4, and MINK1 with pIC₅₀ values of 6.8, 6.8, and 6.7 respectively. MAP4K4-IN-7 can be used for the researches of cancer and neurological disease, such as schizophrenia.

HY-123965

PF-06745013	Inhibitor
PF-06745013 (Compound 37) is a MAP4K4 inhibitor without time-dependent inhibition (TDI) risk of CYP3A4 (IC₅₀ of 0.4  nM for MAP4K4). PF-06745013 has no accumulation CNS-impaired and non-ATP competitive activities in mouse models. PF-06745013 can be used for inflammatory diseases like diabetes and cancers research.

HY-172107

HPK1-IN-56	Inhibitor
HPK1-IN-56 (Compound A29) is a HPK1 inhibitor (IC₅₀: 2.70 nM). HPK1-IN-56 inhibits downstream p-SLP76 (IC₅₀: 8.1 nM in Jurkat T cells). HPK1-IN-56 induces the production of IL-2 in human PBMCs. HPK1-IN-56 has anticancer effect, enhances T-cell killing ability and the antitumor efficacy of anti-PD-1 antibody.

HY-151377

RET-IN-19	Inhibitor
RET-IN-19 (compound 59) is a potent RET inhibitor, with IC₅₀ values of 6.8 and 13.51 nM against RET-wt and RET V804M, respectively. RET-IN-19 shows anticancer activity. RET-IN-19 can be used for non-small cell lung cancer (NSCLC) research.

HY-146680

FLT3/ITD-IN-4	Inhibitor
FLT3/ITD-IN-4 (Compound 16) is a selective FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) inhibitor with an IC₅₀ of 2.3 nM. FLT3/ITD-IN-4 can be used for acute myeloid leukemia research.

HY-168110

HPK1-IN-52	Inhibitor
HPK1-IN-52 is a potent and orally active hematopoietic progenitor kinase 1 (HPK1) inhibitor with an IC₅₀ value of 10.4 nM. HPK1-IN-52 exhibits anti-tumor activities.

HY-178775

PI4K-IN-3	Inhibitor
PI4K-IN-3 (Compound 27) is an orally active PI4K inhibitor with an IC₅₀ of 1.9  nM for Plasmodium vivax PI4K. PI4K-IN-3 has no hERG channel inhibition and mammalian cytotoxicity. PI4K-IN-3 has significant selectivity against the human MINK1 and MAP4K4 kinases but with low selectivity against human PI3Kα and PI4Kβ. PI4K-IN-3 has potent antimalarial activity and significantly reduces parasitaemia in NSG mice mouse models of Plasmodium falciparum malaria.

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