LW6

Description: LW6 is a hypoxia-inducible factor 1 (HIF) inhibitor which potently inhibits HIF-1alpha accumulation by degrading HIF-1alpha without affecting the HIF-1a mRNA levels during hypoxia. It inhibits HIF-1alpha transcription activity with IC50 of 2.64 uM in cell-based HRE-reporter gene assays. LW6 decreases HIF-1alpha protein expression without affecting HIF-1beta expression. LW6 affects the stability of the HIF-1alpha protein. LW6 promotes 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. 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.

References: Biochem Pharmacol. 2010 Oct 1; 80(7):982-9; J Med Chem. 2014 Nov 26; 57(22):9522-38; Cancer Chemother Pharmacol. 2016 Oct; 78(4):735-44.