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A POTENT PYRAZOLE-CONTAINING STING ANTAGONIST SYNTHESIZED VIA DOEBNER-POVAROV MULTICOMPONENT REACTION

thesis
posted on 22.04.2022, 18:08 authored by Wei Shiuan Wilson OngWei Shiuan Wilson Ong

  

The cGAS-STING axis represents a key pathway towards the activation of innate immunity against pathogens. However, persistent activation can lead to the development of autoimmune diseases, driving the need for the development of antagonists of cGAS-STING pathway. Herein, we describe the discovery of a small molecule STING binder HSD1077 through a STING based fluorescence polarization (FP) displacement assay. Initial SAR studies utilizing the FP displacement assay suggests the presence of pyrazole moieties critical for HSD1077 towards STING Binding. Additionally, we show that HSD1077 serves as an antagonist of the cGAS-STING pathway and effectively suppresses type-1 interferon expression upon 2’-3’cGAMP induction in both murine RAW macrophages and human THP-1 monocytes. HSD1077 in conclusion shows potential as a lead compound towards the further development of anti-inflammatory drugs. 

History

Degree Type

Master of Science

Department

Chemistry

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

Herman O. Sintim

Additional Committee Member 2

Elizabeth I. Parkinson

Additional Committee Member 3

Shalini T. Low-Nam