The serine/threonine kinase MAP4K4 is a member of the Ste20p (sterile 20 protein) family. The role of MAP4K4 in immunity, inflammation, metabolic and cardiovascular disease has been recognized. Increasing evidence suggests that MAP4K4 plays an important role in cancer and MAP4K4 may represent a novel actionable cancer therapeutic target[1]. GNE-495 is a potent and selective MAP4K4 inhibitor with an IC50 of 3.7 nM. It shows the best balance of MAP4K4 inhibition, permeability, microsomal stability, and cellular potency[2]. GNE-495 is administered intraperitoneally to neonatal mouse pups at high doses: 25 and 50 mg/kg. GNE-495 shows good in vivo profile in all species tested, with low clearances, moderate terminal half-lives, and reasonable oral exposure levels (F=37-47%). GNE-495 showed excellent potency and good PK and was used to demonstrate in vivo efficacy in a retinal angiogenesis model recapitulating effects that were observed in the inducible Map4k4 knockout mice[2].
作用机制
The amide linker extending from the naphthyridine scaffold effectively replaces two of the water molecules and engages in a hydrogen-bonding interaction to the hinge Cys108 carbonyl. Overall, the binding pocket was completely occupied by the optimized ligand.
GNE-495 细胞实验
Cell Line
Concentration
Treated Time
Description
References
AsPC-1
2 µM
24 hours
GNE-495 could not block MLK3 T738D-induced JNK and c-Jun activation
Oncogene. 2021 Oct;40(43):6153-6165
PANC-1
2 µM
24 hours
GNE-495 blocked TNFα-induced activation of JNK and c-Jun
Oncogene. 2021 Oct;40(43):6153-6165
Capan-1
2 µM
24 hours
GNE-495 blocked TNFα-induced activation of JNK and c-Jun
Oncogene. 2021 Oct;40(43):6153-6165
A549
5 µM
48 hours
Inhibited MAP4K4 levels and c-JUN phosphorylation, reversing the enhanced migration and invasion capabilities induced by HMMR overexpression
Int J Biol Sci. 2025 Jan 21;21(4):1391-1409
H1299
5 µM
48 hours
Inhibited MAP4K4 levels and c-JUN phosphorylation, reversing the enhanced migration and invasion capabilities induced by HMMR overexpression
Int J Biol Sci. 2025 Jan 21;21(4):1391-1409
MR cells (radioresistant MCF-7 cells)
500 nM
48 hours
To evaluate the cytotoxic effects of GNE-495 on MR cells, results showed GNE-495 significantly reduced the viability of MR cells.
Sci Rep. 2024 Mar 28;14(1):7410
SR cells (radioresistant SK-BR-3 cells)
500 nM
48 hours
To evaluate the cytotoxic effects of GNE-495 on SR cells, results showed GNE-495 significantly reduced the viability of SR cells.
Sci Rep. 2024 Mar 28;14(1):7410
GNE-495 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mouse
KPC mouse model
Intraperitoneal injection
3 mg/kg body weight
Daily for 3 months
GNE-495 significantly extended the survival of KPC mice, reduced tumor burden, and induced tumor cell death
Oncogene. 2021 Oct;40(43):6153-6165
BALB/c nude mice
LUAD metastasis model
Intraperitoneal injection
3 mg/kg
Once daily for three weeks
GNE-495 treatment effectively reversed the lung metastasis induced by HMMR overexpression
Int J Biol Sci. 2025 Jan 21;21(4):1391-1409
Mice
Retinal vascular development model
Intraperitoneal injection
25 and 50 mg/kg
Daily from P1 to P5 or P6
To evaluate the antiangiogenic effects of GNE-495 in vivo, results showed GNE-495 dose-dependently delayed retinal vascular outgrowth and induced abnormal retinal vascular morphology
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