%0 Generic
%A Bodle, Christopher
R.
%A I. Mackie, Duncan
%A Hayes, Michael P.
%A Schamp, Josephine H
%A Miller, Michael R.
%A D. Henry, Michael
%A Doorn, Jonathan A.
%A C. D. Houtman, Jon
%A A. James, Michael
%A L. Roman, David
%D 2017
%T Natural Products Discovered in a High-Throughput Screen
Identified as Inhibitors of RGS17 and as Cytostatic and Cytotoxic
Agents for Lung and Prostate Cancer Cell Lines
%U https://acs.figshare.com/articles/dataset/Natural_Products_Discovered_in_a_High-Throughput_Screen_Identified_as_Inhibitors_of_RGS17_and_as_Cytostatic_and_Cytotoxic_Agents_for_Lung_and_Prostate_Cancer_Cell_Lines/5116255
%R 10.1021/acs.jnatprod.7b00112.s001
%2 https://ndownloader.figshare.com/files/8687572
%K nanomolar
%K cytostatic
%K compound
%K cysteine reactivity assessment
%K Prostate Cancer Cell Lines Regulator
%K tumor cell proliferation
%K RGS 17
%K High-Throughput Screen Identified
%K IC 50 values
%K micromolar dissociation constants
%K cytotoxic
%K ITC
%K G Protein Signaling
%K prostate cancer cell lines
%X Regulator of G Protein Signaling
(RGS) 17 is an overexpressed promoter
of cancer survival in lung and prostate tumors, the knockdown of which
results in decreased tumor cell proliferation in vitro. Identification
of drug-like molecules inhibiting this protein could ameliorate the
RGS17’s pro-tumorigenic effect. Using high-throughput screening,
a chemical library containing natural products was interrogated for
inhibition of the RGS17–Gαo interaction. Initial
hits were verified in control and counter screens. Leads were characterized
via biochemical, mass spectrometric, Western blot, microscopic, and
cytotoxicity measures. Four known compounds (1–4) were identified with IC50 values ranging from
high nanomolar to low micromolar. Three compounds were extensively
characterized biologically, demonstrating cellular activity determined
by confocal microscopy, and two compounds were assessed via ITC exhibiting
high nanomolar to low micromolar dissociation constants. The compounds
were found to have a cysteine-dependent mechanism of binding, verified
through site-directed mutagenesis and cysteine reactivity assessment.
Two compounds, sanguinarine (1) and celastrol (2), were found to be cytostatic against lung and prostate
cancer cell lines and cytotoxic against prostate cancer cell lines
in vitro, although the dependence of RGS17 on these phenomena remains
elusive, a result that is perhaps not surprising given the multimodal
cytostatic and cytotoxic activities of many natural products.
%I ACS Publications