Enhanced Suppression of a Protein–Protein Interaction in Cells Using Small-Molecule Covalent Inhibitors Based on an N-Acyl-N-alkyl Sulfonamide Warhead

2021 ◽  
Author(s):  
Tsuyoshi Ueda ◽  
Tomonori Tamura ◽  
Masaharu Kawano ◽  
Keiya Shiono ◽  
Fruzsina Hobor ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Interaction ◽  
Protein Protein Interaction ◽  
Covalent Inhibitors ◽  
In Cells

scholarly journals Development of a Novel High-Throughput Screen and Identification of Small-Molecule Inhibitors of the Gα–RGS17 Protein–Protein Interaction Using AlphaScreen

2011 ◽  
Vol 16 (8) ◽  
pp. 869-877 ◽  
Author(s):  
Duncan I. Mackie ◽  
David L. Roman
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
Protein Interaction ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Screening Method ◽  
Fold Increase ◽  
Rgs Proteins ◽  
High Throughput Screen ◽  
Protein Protein Interaction

In this study, the authors used AlphaScreen technology to develop a high-throughput screening method for interrogating small-molecule libraries for inhibitors of the Gαo–RGS17 interaction. RGS17 is implicated in the growth, proliferation, metastasis, and the migration of prostate and lung cancers. RGS17 is upregulated in lung and prostate tumors up to a 13-fold increase over patient-matched normal tissues. Studies show RGS17 knockdown inhibits colony formation and decreases tumorigenesis in nude mice. The screen in this study uses a measurement of the Gαo–RGS17 protein–protein interaction, with an excellent Z score exceeding 0.73, a signal-to-noise ratio >70, and a screening time of 1100 compounds per hour. The authors screened the NCI Diversity Set II and determined 35 initial hits, of which 16 were confirmed after screening against controls. The 16 compounds exhibited IC50 <10 µM in dose–response experiments. Four exhibited IC50 values <6 µM while inhibiting the Gαo–RGS17 interaction >50% when compared to a biotinylated glutathione-S-transferase control. This report describes the first high-throughput screen for RGS17 inhibitors, as well as a novel paradigm adaptable to many other RGS proteins, which are emerging as attractive drug targets for modulating G-protein-coupled receptor signaling.

Probing the Small-Molecule Inhibition of an Anticancer Therapeutic Protein-Protein Interaction Using a Solid-State Nanopore

2016 ◽  
Vol 128 (19) ◽  
pp. 5807-5811 ◽  
Author(s):  
Dong-Kyu Kwak ◽  
Hongsik Chae ◽  
Mi-Kyung Lee ◽  
Ji-Hyang Ha ◽  
Gaurav Goyal ◽  
...  
Keyword(s):  
Solid State ◽  
Small Molecule ◽  
Protein Interaction ◽  
Therapeutic Protein ◽  
Protein Protein Interaction ◽  
Small Molecule Inhibition

Small-Molecule Stabilization of the 14-3-3/Gab2 Protein-Protein Interaction (PPI) Interface

ChemMedChem ◽  
2015 ◽  
Vol 11 (8) ◽  
pp. 911-918 ◽  
Author(s):  
David Bier ◽  
Maria Bartel ◽  
Katharina Sies ◽  
Sebastian Halbach ◽  
Yusuke Higuchi ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Interaction ◽  
Protein Protein Interaction

scholarly journals CHI PMUNK: A Virtual Synthesizable Small-Molecule Library for Medicinal Chemistry, Exploitable for Protein-Protein Interaction Modulators

ChemMedChem ◽  
2018 ◽  
Vol 13 (6) ◽  
pp. 532-539 ◽  
Author(s):  
Lina Humbeck ◽  
Sebastian Weigang ◽  
Till Schäfer ◽  
Petra Mutzel ◽  
Oliver Koch
Keyword(s):  
Small Molecule ◽  
Protein Interaction ◽  
Medicinal Chemistry ◽  
Protein Protein Interaction ◽  
Small Molecule Library
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