LW6

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LW6 是一种新型 HIF-1 抑制剂。

CAY10585, also known as LW6, was first identified and reported by a group scientists from Korea. LW8 was found to inhibits the accumulation of HIF-1alpha. LW6 decreased HIF-1alpha protein expression without affecting HIF-1beta expression. It was further found that LW8 promoted the degradation of wild type HIF-1alpha, but not of a DM-HIF-1alpha with modifications of P402A and P564A, at hydroxylation sites in the oxygen-dependent degradation domain (ODDD). LW6 did not affect the activity of prolyl hydroxylase (PHD), but induced the expression of von Hippel-Lindau (VHL), which interacts with prolyl-hydroxylated HIF-1alpha for proteasomal degradation. In the presence of LW8, knockdown of VHL did not abolish HIF-1alpha protein accumulation, indicating that LW8 degraded HIF-1alpha via regulation of VHL expression. In mice carrying xenografts of human colon cancer HCT116 cells, LW8 demonstrated strong anti-tumor efficacy in vivo and caused a decrease in HIF-1alpha expression in frozen-tissue immunohistochemical staining. These data suggest that LW8 may be valuable in the development of a HIF-1alpha inhibitor for cancer treatment.

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. 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. LW6 inhibits the expression of HIF 1α induced by hypoxia in A549 cells at 20 μM, independently of the von Hippel Lindau protein. LW6 induces hypoxia selective apoptosis together with a reduction in the mitochondrial membrane potential.

In mice carrying xenografts of human colon cancer HCT116 cells, LW6 demonstrates strong anti-tumor efficacy in vivo and causes a decrease in HIF-1α expression in frozen-tissue immunohistochemical staining.

CAY10585 | CAY-10585 | CAY 10585 | LW6

Others

Other Targets

HIF-1

Cancer

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934593-90-5

435.52

C26H29NO5

>98% (HPLC)

DMSO : ≥ 33 mg/mL; 75.77 mM

O=C(OC)C1=CC=C(O)C(NC(COC2=CC=C(C3(C4)CC5CC4CC(C5)C3)C=C2)=O)=C1

methyl 3-(2-(4-(adamantan-1-yl)phenoxy)acetamido)-4-hydroxybenzoate

(-20℃)

With Ice Pack

≥ 2 years