Sarmadi Fatemeh, Caza Amelia, Gao Zhizhong, Rochel Natacha, Gleason James L, White John H
Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada.
Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, QC H3A 0B8, Canada.
J Med Chem. 2025 Oct 9;68(19):20675-20688. doi: 10.1021/acs.jmedchem.5c01932. Epub 2025 Sep 18.
1,25-Dihydroxyvitamin D (1,25D) analogs engage the vitamin D receptor (VDR) and can exert anticancer and immunomodulatory effects. Although tumors often resist 1,25D monotherapy, combining VDR agonism with histone deacetylase inhibitors (HDACi) restores anticancer efficacy. Here, we present AC-340, a novel bifunctional molecule that incorporates HDACi into a VDR agonist backbone. Besides its robust bifunctionality in vitro in multiple melanoma models, RNaseq analysis of B16-F10 mouse melanoma cells revealed that AC-340 superinduces the expression of a broad array of VDR target genes. Comparative structural studies and ChIP-qPCR revealed that AC-340 forms more interactions than 1,25D with residues in the VDR coactivator binding domain, leading to more efficacious recruitment of coactivator CBP. This, likely coupled with AC-340 HDACi activity, leads to elevated H3K27 acetylation of VDR target genes, a mark of active transcription. Thus, AC-340 functions as a VDR hyperagonist and should be efficacious in mono- or combination therapies against multiple cancer models.
1,25-二羟基维生素D（1,25D）类似物可与维生素D受体（VDR）结合，并发挥抗癌和免疫调节作用。尽管肿瘤通常对1,25D单一疗法产生耐药性，但将VDR激动剂与组蛋白脱乙酰酶抑制剂（HDACi）联合使用可恢复抗癌疗效。在此，我们介绍AC-340，一种新型双功能分子，它将HDACi整合到VDR激动剂骨架中。除了在多种黑色素瘤模型中具有强大的体外双功能外，对B16-F10小鼠黑色素瘤细胞的RNA测序分析表明，AC-340能超诱导大量VDR靶基因的表达。比较结构研究和染色质免疫沉淀定量PCR（ChIP-qPCR）显示，AC-340与VDR共激活因子结合域中的残基形成的相互作用比1,25D更多，从而更有效地招募共激活因子CBP。这可能与AC-340的HDACi活性相结合，导致VDR靶基因的H3K27乙酰化水平升高，这是活跃转录的标志。因此，AC-340作为一种VDR超激动剂，在针对多种癌症模型的单一疗法或联合疗法中应该是有效的。
