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High‐Throughput Screening for Inhibitors of RGS17: A novel target for treatment of lung and prostate cancers
Author(s) -
Mackie Duncan Ian,
Roman David L.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.802.2
Subject(s) - medicine , prostate cancer , prostate , oncology , throughput , lung , cancer research , cancer , computer science , telecommunications , wireless
RGS17 is implicated in the growth, proliferation, metastasis and the migration of prostate and lung cancers. RGS17 is up‐regulated in lung and prostate tumor tissues by 13 fold over patient‐matched normal tissues. Reports indicate that RGS17 knockdown inhibits colony formation and decreases tumorigenesis in mice. In this study, we implemented AlphaScreen technology to develop a high‐throughput screening method for interrogating small molecule libraries for inhibitors of RGS17. Our screen utilizes a measurement of the Gα:RGS17 interaction, with an excellent Z‐score exceeding 0.73, a signal to noise ratio >70 and a screening time of 1,100 compounds per hour. We screened the NCI Diversity Set II and determined 35 initial hits and 16 were confirmed after screening against controls. The 16 compounds exhibited IC50 <10μM in dose‐response experiments for inhibiting the Gα:RGS17 interaction. Four exhibited IC50 values <6μM while inhibiting the Gα:RGS17 interaction >50% when compared to a biotinylated GST control. Immediate goals include determining the effectiveness of these compounds on inhibiting GTPase acceleration activity of RGS17 in single turnover GTPase assays and testing structurally related compounds for inhibition. This study is to establish lead compounds and develop a pharmacophore model for optimization of structure. Supported by American Cancer Society ‐ Holden Comprehensive Research Center.