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Potent, Selective and Cell Penetrant Inhibitors of SF-1 by Functional Ultra-High-Throughput Screening

Scripps Research Molecular Screening Center (F.M., P.C., P.R.G., P.H.), Translational Research Institute (F.M., P.C., G.Z., M.D.C., J.C., P.R.G., P.S.H.), and Molecular Therapeutics (P.R.G., P.H.), The Scripps Research Institute, Scripps Florida, Jupiter, Florida; and Orphagen Pharmaceuticals, San Diego California (X.L., S.T.)

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 IC₅₀ 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 IC₅₀ 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.

Address correspondence to: Prof. Peter Hodder, Director and Head, HTS Lead Identification Department, Scripps Florida, 5353 Parkside Drive RFA-6, Jupiter, FL 33458-2906. E-mail: hodderp{at}scripps.edu