Fischer Joshua, Wang Tian-Tian, Kaldre Dainis, Rochel Natacha, Moras Dino, White John H, Gleason James L
Department of Chemistry, McGill University, Montreal, Quebec H3A 0G4, Canada.
Chem Biol. 2012 Aug 24;19(8):963-71. doi: 10.1016/j.chembiol.2012.05.024.
1,25-Dihydroxyvitamin D(3) (1,25D), the hormonal form of vitamin D, and several analogs have failed as monotherapies for cancer because of poor efficacy or acquired resistance. However, 1,25D analogs are amenable to bifunctionalization. Preclinical studies have revealed combinatorial effects of 1,25D analogs and histone deacetylase inhibitors (HDACi). Secosteroidal hybrid molecules combining vitamin D receptor (VDR) agonism with HDACi displayed enhanced efficacy but are laborious to synthesize. Here, we have developed easily assembled, fully integrated, non-secosteroidal VDR agonist/HDACi hybrids. The most promising are full VDR agonists with ~10-fold lower potency than 1,25D. Structure/function studies revealed that antiproliferative activity against 1,25D-resistant squamous carcinoma cells required VDR agonism and HDACi. Remarkably, modeling and X-ray crystallography reveal non-secosteroidal hybrids bind in the VDR ligand binding domain in the opposite orientation of their secosteroidal counterparts.
1,25-二羟基维生素D(3)(1,25D)作为维生素D的激素形式，以及几种类似物，由于疗效不佳或获得性耐药，作为癌症单一疗法均告失败。然而，1,25D类似物适合进行双功能化。临床前研究揭示了1,25D类似物与组蛋白去乙酰化酶抑制剂(HDACi)的联合效应。将维生素D受体(VDR)激动作用与HDACi相结合的甾醇类杂交分子显示出增强的疗效，但合成过程繁琐。在此，我们开发了易于组装、完全整合的非甾醇类VDR激动剂/HDACi杂交分子。最有前景的是效力比1,25D低约10倍的完全VDR激动剂。结构/功能研究表明，对1,25D耐药的鳞状癌细胞的抗增殖活性需要VDR激动作用和HDACi。值得注意的是，建模和X射线晶体学显示，非甾醇类杂交分子在VDR配体结合域中的结合方向与其甾醇类对应物相反。
