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Synthetically accessible non-secosteroidal hybrid molecules combining vitamin D receptor agonism and histone deacetylase inhibition.

Fischer J, Wang TT, Kaldre D, Rochel N, Moras D, White JH, Gleason JL
Chem Biol 19 963-71 (2012)
Cited: 13 times
EuropePMC logo PMID: 22921063

Abstract

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.

Reviews citing this publication (8)

  1. Advances in the development of hybrid anticancer drugs. Fortin S, Bérubé G. Expert Opin Drug Discov 8 1029-1047 (2013)
  2. Vitamin D in cancer chemoprevention. Giammanco M, Di Majo D, La Guardia M, Aiello S, Crescimannno M, Flandina C, Tumminello FM, Leto G. Pharm Biol 53 1399-1434 (2015)
  3. Epigenetic polypharmacology: from combination therapy to multitargeted drugs. de Lera AR, Ganesan A. Clin Epigenetics 8 105 (2016)
  4. Vitamin D and Its Synthetic Analogs. Maestro MA, Molnár F, Carlberg C. J Med Chem 62 6854-6875 (2019)
  5. Multitarget Drugs: an Epigenetic Epiphany. Ganesan A. ChemMedChem 11 1227-1241 (2016)
  6. Structural considerations of vitamin D signaling. Molnár F. Front Physiol 5 191 (2014)
  7. Structure-activity relationship of nonsecosteroidal vitamin D receptor modulators. Yamada S, Makishima M. Trends Pharmacol Sci 35 324-337 (2014)
  8. The Centennial Collection of VDR Ligands: Metabolites, Analogs, Hybrids and Non-Secosteroidal Ligands. Maestro MA, Seoane S. Nutrients 14 4927 (2022)

Articles citing this publication (5)

  1. A chimeric SERM-histone deacetylase inhibitor approach to breast cancer therapy. Patel HK, Siklos MI, Abdelkarim H, Mendonca EL, Vaidya A, Petukhov PA, Thatcher GR. ChemMedChem 9 602-613 (2014)
  2. Efficacy of hybrid vitamin D receptor agonist/histone deacetylase inhibitors in vitamin D-resistant triple-negative 4T1 breast cancer. Bijian K, Kaldre D, Wang TT, Su J, Bouttier M, Boucher A, Alaoui-Jamali M, White JH, Gleason JL. J Steroid Biochem Mol Biol 177 135-139 (2018)
  3. Editorial Histone deacetylases inhibitors: conjugation to other anti-tumour pharmacophores provides novel tools for cancer treatment. Papavassiliou KA, Papavassiliou AG. Expert Opin Investig Drugs 23 291-294 (2014)
  4. Optimization of histone deacetylase inhibitor activity in non-secosteroidal vitamin D-receptor agonist hybrids. Kaldre D, Wang TT, Fischer J, White JH, Gleason JL. Bioorg Med Chem 23 5035-5049 (2015)
  5. Molecular mechanisms of bifunctional vitamin D receptor agonist-histone deacetylase inhibitor hybrid molecules in triple-negative breast cancer. Barbier C, Mansour A, Ismailova A, Sarmadi F, Scarlata DA, Bouttier M, Zeitouni C, Wang C, Gleason JL, White JH. Sci Rep 12 6745 (2022)


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