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Potent, selective and cell penetrant inhibitors of SF-1 by functional ultra-high-throughput screening

Academic Article
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Overview

authors

  • Madoux, F.
  • Li, X. L.
  • Chase, P.
  • Zastrow, G.
  • Cameron, Michael
  • Conkright, J. J.
  • Griffin, Patrick
  • Thacher, S.
  • Hodder, Peter

publication date

  • June 2008

journal

  • Molecular Pharmacology  Journal

abstract

  • The steroidogenic factor 1 (SF-1, also known as NR5A1) is a transcription factor belonging to the nuclear receptor superfamily. Whereas most of the members of this family have been extensively characterized, the therapeutic potential and pharmacology of SF-1 still remains elusive. Described here is the identification and characterization of selective inhibitory chemical probes of SF-1 by a rational ultra-high-throughput screening (uHTS) strategy. A set of 64,908 compounds from the National Institute of Health's Molecular Libraries Small Molecule Repository was screened in a transactivation cell-based assay employing a chimeric SF-1 construct. Two analogous isoquinolinones, ethyl 2-[2-[2-(2,3-dihydro-1,4-benzodioxin-7-ylamino)-2-oxoethyl]-1-oxoisoquinolin-5-yl]oxypropanoate (SID7969543) and ethyl 2-[2-[2-(1,3-benzodioxol-5-ylmethylamino)-2-oxoethyl]-1-oxoisoquinolin-5-yl]oxypropanoate and (SID7970631), were identified as potent submicromolar inhibitors, yielding IC(50) values of 760 and 260 nM. The compounds retained their potency in a more physiologic functional assay employing the full-length SF-1 protein and its native response element, yielding IC(50) values of 30 and 16 nM, respectively. The selectivity of these isoquinolinones was confirmed via transactivation-based functional assays for RAR-related orphan receptor A (RORA), Herpes simplex virus transcriptional activator protein Vmw65 (VP16), and liver receptor homolog 1 (LRH-1). Their cytotoxicity, solubility, permeability and metabolic stability were also measured. These isoquinolinones represent valuable chemical probes to investigate the therapeutic potential of SF-1.

subject areas

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dogs
  • Haplorhini
  • Humans
  • Isoquinolines
  • Mice
  • Rats
  • Small Molecule Libraries
  • Steroidogenic Factor 1
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Identity

PubMed Central ID

  • PMC3228235

International Standard Serial Number (ISSN)

  • 0026-895X

Digital Object Identifier (DOI)

  • 10.1124/mol.108.045963

PubMed ID

  • 18334597
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Additional Document Info

start page

  • 1776

end page

  • 1784

volume

  • 73

issue

  • 6

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