Figure 1.
Discovery and optimization of dualHIFi. (A) Overview of the workflow is presented. (B) Crystal structure of HIF-2α–HIF-1β was analyzed using SILCS, which identified three potential ligand binding sites. (C) Models of site 1 and site 3 occupancy by SS1.21 and SS3.2, respectively, are shown. (D) Highly conserved domain organization of HIF-1α and HIF-2α is shown with location of candidate ligand binding sites indicated by red brackets. (E) Chemical structures of dual HIFi are shown. SS1.21 and derivative compound 1.21S9N bind to site 1, whereas SS3.2 and derivative compound 3.2.16 bind to site 3. (F and G) Expression of CA9 (F) and EPO (G) mRNA was analyzed in Hep3B cells incubated for 24 h at 20% or 1% O2 with vehicle, or at 1% O2 with the indicated HIF inhibitor at the indicated concentration (μM), and derived IC50 values are shown. Results are presented as the mean ± SD (n = 3). #P < 0.05 versus 1% O2 (vehicle); ns, no significant difference versus 1% O2 (vehicle); two-way ANOVA with Dunnett’s multiple comparisons post-test. Refer to the image caption for details. The multiple graphs and diagrams are related to the discovery and optimization of dual H I F-1 over 2 inhibitors. Panel A shows a workflow diagram outlining the steps from S I L C S in silico screen to mouse tumor models. Panel B displays the crystal structure of H I F-2 alpha bound to H I F-1 beta, with three potential ligand binding sites identified. Panel C presents models of site 1 and site 3 occupancy by S S 1.21 and S S 3.2, respectively. Panel D illustrates the domain organization of H I F-1 alpha and H I F-2 alpha, highlighting the locations of candidate ligand binding sites. Panel E shows the chemical structures of dual H I F-1 over 2 inhibitors, indicating which compounds bind to site 1 and site 3. Panels F and G are bar graphs showing the expression of C A 9 and E P O m R N A in H e p 3 B cells under different conditions and concentrations of H I F inhibitors. The graphs include mean values with standard deviations, and statistical significance is indicated. All values are approximate.

Discovery and optimization of dual HIFi . (A) Overview of the workflow is presented. (B) Crystal structure of HIF-2α–HIF-1β was analyzed using SILCS, which identified three potential ligand binding sites. (C) Models of site 1 and site 3 occupancy by SS1.21 and SS3.2, respectively, are shown. (D) Highly conserved domain organization of HIF-1α and HIF-2α is shown with location of candidate ligand binding sites indicated by red brackets. (E) Chemical structures of dual HIFi are shown. SS1.21 and derivative compound 1.21S9N bind to site 1, whereas SS3.2 and derivative compound 3.2.16 bind to site 3. (F and G) Expression of CA9 (F) and EPO (G) mRNA was analyzed in Hep3B cells incubated for 24 h at 20% or 1% O2 with vehicle, or at 1% O2 with the indicated HIF inhibitor at the indicated concentration (μM), and derived IC50 values are shown. Results are presented as the mean ± SD (n = 3). #P < 0.05 versus 1% O2 (vehicle); ns, no significant difference versus 1% O2 (vehicle); two-way ANOVA with Dunnett’s multiple comparisons post-test.

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