Potent, selective and cell penetrant inhibitors of SF-1 by functional ultra-high-throughput screening
| Autor: | Michael D. Cameron, Juliana J. Conkright, Gina M. Zastrow, Peter Hodder, Xiaolin Li, Patrick R. Griffin, Franck Madoux, Scott Thacher, Peter Chase |
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| Rok vydání: | 2008 |
| Předmět: |
Pharmacology
Orphan receptor Chinese hamster ovary cell Liver receptor homolog-1 High-throughput screening CHO Cells Haplorhini Biology Isoquinolines Steroidogenic Factor 1 Molecular biology Small molecule Article Rats Small Molecule Libraries Transactivation Mice Cricetulus Dogs Nuclear receptor Cricetinae Molecular Medicine Animals Humans Cytotoxicity |
| Zdroj: | Molecular pharmacology. 73(6) |
| ISSN: | 1521-0111 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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