描述

Ca2+/calmodulin-dependent protein kinases (CaM-Ks) are a large group of enzymes involved in cellular responses mediated by an increase of intracellular calcium. They can be activated by an upstream CaM kinase kinase (CaM-KK) that consists of two isoforms. STO-609 inhibits the activities of recombinant CaM-KKα and CaM-KKβ with IC50 values of 120 and 40 ng/ml, and Ki values of 80 and 15 ng/ml, respectively. In HeLa cells transfected with CaM-KIV cDNA, treatment with 10 μg/ml STO-609 for 6 hours inhibited the activation of CaM-KIV by ~90%. The incubation with 0.1 μg/ml STO-609 for 6 hours suppressed the activation of CaM-KIV 50~60% in SH-SY5Y cells infected with a constitutively active CaM-KIV, whereas 1 μg/ml STO-609 resulted in ~80% inhibition. STO-609 inhibited the protein kinase activity of wild-type CaM-KKβ expressed in COS-7 cells with an IC50 value of 20–30 ng/ml. STO-609 at 1 g/ml suppressed 40% of CaM-KK activity in COS-7 cells expressing CaM-KKβ V269F mutant. Six-hour treatment with 25 μM STO-609 induced mRNA and protein expressions of CYP1A1 in MCF-7 cells. In lung A549 cells, 25 μM STO-609 induced CYP1A1 activity and concomitantly inhibited CaM-KK activity-mediated phosphorylation of AMPKα 6 hours post treatment. STO-609 at 25 μM also upregulated various AhR target genes such as ITGB7, CYP1B1, and IL8 in primary human macrophages after 6-hour incubation.

作用机制

STO-609 permeates cells and competes with ATP to bind to the ATP-binding pocket on CaM-KK, thereby preventing them from activating the phosphorylation of CaM kinases.

CAS

52029-86-4

分子式

C₁₉H₁₀N₂O₃

分子量

314.29

溶解度

DMSO：5.0 mg/mL (15.9 mM) warming，water：insoluble

动物实验配方

IP 2% DMSO+water，0.1 mg/mL clear

PO 0.5% CMC-Na，36 mg/mL suspension

结构式