LW6 decreased HIF-1alpha protein expression without affecting HIF-1beta expression. LW6 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 mice carrying xenografts of human colon cancer HCT116 cells, LW6 demonstrated strong anti-tumor efficacy in vivo and caused a decrease in HIF-1alpha expression in frozen-tissue immunohistochemical staining.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: ≥ 20 mg/mL|
Discovery of LW6 as a new potent inhibitor of breast cancer resistance protein.
Song JG, et al. Cancer Chemother Pharmacol. 2016 Oct;78(4):735-44. PMID: 27520631.
LW6, a hypoxia-inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells.
Sato M, et al. Mol Med Rep. 2015 Sep;12(3):3462-3468. PMID: 26017562.
LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1alpha via upregulation of VHL in a colon cancer cell line.
Lee K, et al. Biochem Pharmacol. 2010 Oct 1;80(7):982-9. PMID: 20599784.
|Related HIF Products|
Enarodustat (JTZ-951) is a potent and orally active factor prolyl hydroxylase inhibitor, with an EC50 of 0.22 μM.
PT2385 is an orally active, selective inhibitor of hypoxia inducible factor (HIF)-2alpha, with a Ki value of less than 50 nM.
JNJ-42041935 is a potent, competitive, reversible, and selective inhibitor of PHD with pKi values of 7.91±0.04, 7.29 ±0.05, and 7.65±0.09 for PHD1, PHD2, and PHD3, respectively.
Daprodustat (GSK1278863) is a novel, orally active HIF-prolyl hydroxylase inhibitor.
BIQ (FG-2216) is an orally available and potent inhibitor of prolyl-hydroxylase (PHD) with IC50 of 3.9 uM for PDH2 enzyme.
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