HIF-1/2α-IN-1, an orally active compound, functions as an inhibitor of HIF-2α. Its inhibitory effect on HIF-2α activity is significant, with an IC 50 value of 0.92 μM. Furthermore, HIF-1/2α-IN-1 has the ability to decrease HIF-1α levels. This compound is particularly valuable for research on clear cell renal cell carcinoma (ccRCC) [1].

HIF-1/2α-IN-1 (compound #25) effectively inhibits HIF-2α with an IC50 of 0.92 µM across 0.01-100 µM concentrations. At 0-10 µM over 24 hours, it reduces HIF-2α levels by inhibiting IRE-dependent translation and targets HIF-1α at higher concentrations through ISCA2 function suppression. At 1 µM for 24 hours, it specifically targets ISCA2, inducing an iron starvation response. The compound significantly reduces cell viability in 786-0 and RCC4 cell lines, with IC50 values of 1.7 µM and 4.8 µM, respectively, and affects viability at elevated levels in VHL versions of these cells. Experimental findings show decreased cell viability, reduced HIF-2α activity and protein levels, and lower HIF-1α levels without promoting proteasomal degradation, along with dose-dependent upregulation of IRP2 and TFRC and a decrease in FTH. RT-PCR results indicate a dose-dependent reduction in the transcription of HIF-2α target genes VEGFA and POU5F1 without affecting HIF-2α transcription.

HIF-1/2α-IN-1 (compound #25), administered orally at 30 and 60 mg/kg daily, significantly inhibited clear cell renal cell carcinoma (ccRCC) xenograft growth in 6-8 week old male NRG or Balb/c mice (10 per group), showing good tolerance without notable weight loss.