AC-340 is a potent hybrid molecule functioning as a VDR agonist and HDAC inhibitor. It can significantly induce the expression of VDR target genes such as CYP24A1, with a selectivity for HDAC2 approximately 10 times greater than for HDAC6 (IC50= 0.37 μM). By causing extensive protein hyperacetylation, such as that of tubulin and H3K9/K27, AC-340 enhances VDR superagonism, resulting in increased acetylation levels of H3K27 on VDR target genes. AC-340 is applicable in research related to melanoma.

HDAC6:0.37 μM

AC-340 (10 μM, 6 hours) significantly induces protein hyperacetylation in B16-F10 cells, including tubulin acetylation (targeted by HDAC6) and acetylation of histone H3 at lysines 9 and 27. When applied at 10 μM for 24 hours, AC-340 upregulates VDR gene and protein expression in mouse B16-F10 cells, while in human A375 and SK-MEL-28 cells, it only enhances VDR protein expression without affecting gene expression. AC-340 induces VDR recruitment to Spp1 VDRE within 2 hours, resembling levels seen with Calcitriol (1,25D), but uniquely induces significant H3K27 acetylation at this site in B16-F10 cells. AC-340 interacts with VDR more extensively than the natural ligand 1,25D by forming a broader interaction with the coactivator-binding surface.