LW6

LW6 (HIF-1α inhibitor) is a novel HIF-1 inhibitor with an IC₅₀ value of 4.4 μM, and it is also an inhibitor of MDH2. LW6 decreases HIF-1α protein expression without affecting HIF-1β expression. IC50 & Target:IC50: 4.4 μM (HIF-1)^[1] In Vitro:LW6 (0-20 μM; 12-16 h) 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].
LW6 (0.01-25 µM; 0-48 h) enhances significantly the cellular accumulation of mitoxantrone, a BCRP substrate in MDCKII-BCRP cells overexpressing BCRP. LW6 also down-regulates BCRP expression at concentrations of 0.1-10 μM^[3].
LW6 (5-100 μM; 12-48 h) 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^[4]. In Vivo:LW6 (intraperitoneal injection; 10-20 mg/kg; 13 days) demonstrates strong anti-tumor efficacy in vivo and causes a decrease in HIF-1α expression in frozen-tissue immunohistochemical staining in mice carrying xenografts of human colon cancer HCT116 cells^[2].