Discovery of 3-(Fluoro-imidazolyl)pyridazine Derivatives as Potent STING Agonists with Antitumor Activity.

Stimulator of interferon genes (STING) represents a promising therapeutic target for cancer and infectious diseases due to its ability to activate innate immune responses. Herein, we describe the discovery of 3-(fluoro-imidazolyl) pyridazine derivatives as potent STING agonists. Our comprehensive investigation, including structural and functional analysis as well as molecular dynamics simulation, suggests that appropriate spatial dimensions may play a crucial role in determining agonist efficacy.

Discovery of an Orally Bioavailable STING Inhibitor with In Vivo Anti-Inflammatory Activity in Mice with STING-Mediated Inflammation.

The cyclic GMP-AMP synthase (cGAS)-stimulator of the interferon genes (STING) pathway plays a key role in triggering interferon and inflammatory responses against microbial invasion or tumor. However, aberrant activation of the cGAS-STING pathway is associated with a variety of inflammatory and autoimmune diseases, and thus inhibition of STING is regarded as a potential new approach to treating these diseases. Herein, we report a series of novel indolyl-urea derivatives as STING inhibitors.

Design, synthesis, and structure-activity relationship studies of triazolo-pyrimidine derivatives as WRN inhibitors for the treatment of MSI tumors.

Werner syndrome RecQ helicase (WRN), a member of the RecQ helicase family, has recently been identified as a synthetic lethal target in microsatellite instability (MSI) tumors. The triazolo-pyrimidine compound HRO761 is the first WRN inhibitor to enter clinical trials, but research on this scaffold remains limited. Here, we designed a series of derivatives to systematically study the structure-activity relationship (SAR) of triazolo-pyrimidine scaffolds, leading to the discovery of compound S35.

Structure-Activity Relationship Study of 1-Pyrrole-3-carbonitrile Derivatives as STING Receptor Agonists.

The use of small agonists to target stimulators of interferon genes (STING) has been demonstrated to be a promising strategy for the treatment of various cancers and infectious diseases. Herein, we discovered a series of 1-pyrrole-3-carbonitrile derivatives as potential STING agonists. On this basis, the structure-activity relationship of this scaffold was studied by introducing various substituents on the aniline ring system.

Sequence-based drug design as a concept in computational drug design.

Drug development based on target proteins has been a successful approach in recent decades. However, the conventional structure-based drug design (SBDD) pipeline is a complex, human-engineered process with multiple independently optimized steps. Here, we propose a sequence-to-drug concept for computational drug design based on protein sequence information by end-to-end differentiable learning.

The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-κB-mediated inflammation.

Background And Purpose: Psoriasis is a chronic inflammatory skin disease associated with both innate and adaptive immune responses. The stimulator of interferon genes (STING) protein engages in sensing of cytosolic DNA to initiate dsDNA-driven immune responses. In vitro and in vivo anti-psoriasis effects of STING antagonist H-151 were explored.

Cu-Catalyzed Dimerization of Indole Derived Oxime Acetate for Synthesis of Biimidazo[1,2-]indoles.

A copper-mediated cyclization and dimerization of indole derived oxime acetate was developed to generate a series of biimidazo[1,2-]indole scaffolds with two contiguous stereogenic quaternary carbons in one step.