LW6

"目录号: HY-13671

Metabolic Enzyme/Protease-

LW6是新颖的HIF-1抑制剂，IC50值为4.4 μM。

HIF/HIF Prolyl-Hydroxylase

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PT-2385-FG-4592-DMOG-PX-478-2-Methoxyestradiol-BAY 87-2243-Daprodustat-DASA-58-IOX2-Molidustat-FG-2216-JNJ-42041935-Paeoniflorin-Vadadustat-Oltipraz-

生物活性

Description

LW6 is a novelHIF-1inhibitor with anIC50of 4.4 μM.

IC50& Target

IC50: 4.4 μM (HIF-1)[1]

In Vitro

LW6 decreases HIF-1α protein expression without affecting HIF-1β expression. LW6 affects the stability of the HIF-1α protein. LW6 promotes the degradation of wild type HIF-1α, but not of a DM-HIF-1α with modifications of P402A and P564A, at hydroxylation sites in the oxygen-dependent degradation domain. LW6 induces the expression of von Hippel-Lindau (VHL), which interacts with prolyl-hydroxylated HIF-1α for proteasomal degradation. In the presence of LW6, knockdown of VHL does not abolish HIF-1α protein accumulation, indicating that LW6 degraded HIF-1α via regulation of VHL expression[2]. In MDCKII-BCRP cells overexpressing BCRP, LW6 enhances significantly the cellular accumulation of mitoxantrone, a BCRP substrate. LW6 also down-regulates BCRP expression at concentrations of 0.1-10 μM[3]. LW6 inhibits the expression of HIF 1α induced by hypoxia in A549 cells at 20 mM, independently of the von Hippel Lindau protein. LW6 induces hypoxia selective apoptosis together with a reduction in the mitochondrial membrane potential[4].

In Vivo

In mice carrying xenografts of human colon cancer HCT116 cells, LW6 demonstrates strong anti-tumor efficacyin vivoand causes a decrease in HIF-1α expression in frozen-tissue immunohistochemical staining[2].

References

[1].Naik R, et al. Synthesis and structure-activity relationship study of chemical probes as hypoxia induced factor-1α/malate dehydrogenase 2 inhibitors. J Med Chem. 2014 Nov 26;57(22):9522-38.

[2].Lee K, et al. LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1alpha via upregulation of VHL in a colon cancer cell line. Biochem Pharmacol. 2010 Oct 1;80(7):982-9.

[3].Song JG, et al. Discovery of LW6 as a new potent inhibitor of breast cancer resistance protein.

[4].Sato M, et al. LW6, a hypoxia-inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells. Mol Med Rep. 2015 Sep;12(3):3462-8.