A pilot, first-in-human, pharmacokinetic study of 9cUAB30 in healthy volunteers.

University of Wisconsin, Madison, WI 53792, USA.
Cancer Prevention Research (Impact Factor: 5.27). 12/2010; 3(12):1565-70. DOI: 10.1158/1940-6207.CAPR-10-0149
Source: PubMed

ABSTRACT 9cUAB30 is a synthetic analog of 9-cis-retinoic acid with chemopreventive activity in cell lines and in animal models. The purpose of this first-in-human evaluation of 9cUAB30 was to evaluate the single-dose pharmacokinetic profile and toxicity of the compound in healthy volunteers at 3 dose levels. This study enrolled 14 patients to receive a single dose of 5, 10, or 20 mg of 9cUAB30. Plasma and urine samples were collected to assess 9cUAB30 concentrations by a validated LC/MS MS method. 9cUAB30 was well tolerated, with 1 patient experiencing grade 2 toxicity and no grade 3 or 4 toxicities reported. T(max) occurred approximately 3 hours after dose administration with the plasma half-life ranging from 2.79 to 7.21 hours. AUC increased linearly across the examined dose range of 5 to 20 mg; C(max) was proportional to the log of the dose. The plasma clearance ranged from 25 to 39 L/h compared to the renal clearance which ranged from 0.018 to 0.103 L/h. 9cUAB30 has a favorable toxicity and pharmacokinetic profile, with oral availability and primarily hepatic metabolism. Further dose ranging studies with once a day dosing are underway.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Retinoic acid (RA) is the major bioactive metabolite of retinol or vitamin A, which induces a spectrum of pleiotropic effects in cell growth and differentiation that are relevant for embryonic development and adult physiology. The RA activity is mediated primarily by members of the retinoic acid receptor (RAR) subfamily, namely RARα, RARβ and RARγ, which belong to the nuclear receptor (NR) superfamily of transcription factors. RARs form heterodimers with members of the retinoid X receptor (RXR) subfamily and act as ligand-regulated transcription factors through binding specific RA response elements (RAREs) located in target genes promoters. RARs also have non-genomic effects and activate kinase signaling pathways, which fine-tune the transcription of the RA target genes. The disruption of RA signaling pathways is thought to underlie the etiology of a number of hematological and non-hematological malignancies, including leukemias, skin cancer, head/neck cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma, pancreatic cancer, liver cancer, glioblastoma and neuroblastoma. Of note, RA and its derivatives (retinoids) are employed as potential chemotherapeutic or chemopreventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. In humans, retinoids reverse premalignant epithelial lesions, induce the differentiation of myeloid normal and leukemic cells, and prevent lung, liver, and breast cancer. Here, we provide an overview of the biochemical and molecular mechanisms that regulate the RA and retinoid signaling pathways. Moreover, mechanisms through which deregulation of RA signaling pathways ultimately impact on cancer are examined. Finally, the therapeutic effects of retinoids are reported.
    Molecular Aspects of Medicine 12/2014; 41. DOI:10.1016/j.mam.2014.12.003 · 10.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: (2E,4E,6Z,8Z)-8-(3',4'-Dihydro-1'(2H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,3,6-octatrienoic acid, 9cUAB30, is a selective rexinoid for the retinoic X nuclear receptors (RXRs). 9cUAB30 displays substantial chemopreventive capacity with little toxicity. Previously we prepared racemic or enantiomerically pure 9cUAB30 homologs with a methyl substitution at the 4-position of the tetralone ring of 9cUAB30. These 4-methyl-UAB30 rexinoids were very potent RXR agonists, but they dramatically increased lipid biosynthesis, which was not observed for 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologs with methyl substitutions at the 5-, 6-, 7-, or 8-positions of the tetralone ring. The syntheses and biological evaluations of these new analogs are reported here along with the X-ray crystal structures of each homolog bound to the ligand binding domain of hRXRα. We demonstrate that each homolog of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. The X-ray crystal structures of the methyl-substituted 9cUAB30 rexinoids bound to hRXRα-LBD were overlaid with each other and with the structure we determined for Targretin. Each rexinoid which induced hyperlipidemia had methyl groups that interacted with Helix 7 residues of the LBD.
    Journal of Medicinal Chemistry 05/2014; 57(12). DOI:10.1021/jm5004792 · 5.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Retinoid X Receptors (RXRs) are obligate partners for several other nuclear receptors, and they play a key role in several signaling processes. Despite being a promiscuous heterodimer partner, this nuclear receptor is a target of therapeutic intervention through activation using selective RXR-agonists (rexinoids). Agonist binding to RXR initiates a large conformational change in the receptor which allows for coactivator recruitment to its surface and enhanced transcription. Here we reveal the structural and dynamical changes produced when a coactivator peptide binds to the human RXR-α ligand binding domain containing two clinically relevant rexinoids, Targretin and 9-cis-UAB30. Our results show the structural changes are very similar for each rexinoid and similar to those for the pan-agonist 9-cis-retinoic acid. The four structural changes involve key residues on helix 3, helix 4, and helix 11 that move from a solvent exposed environment to one that interacts extensively with helix 12. Hydrogen-deuterium exchange mass spectrometry (HDX MS) reveals the dynamics of helices 3, 11 and 12 are significantly decreased when the two rexinoids are bound to the receptor. When the pan-agonist 9-cis-retinoic acid is bound to the receptor, only the dynamics of helices 3 and 11 are reduced. The four structural changes are conserved in all x-ray structures of the RXR ligand binding domain in the presence of agonist and coactivator peptide. They serve as hallmarks for how RXR changes conformation and dynamics in the presence of agonist and coactivator to initiate signaling.
    Journal of Biological Chemistry 11/2013; 289(2). DOI:10.1074/jbc.M113.476861 · 4.60 Impact Factor


1 Download
Available from