# Novel target deconvolution in cGAS-STING pathway

> **NIH NIH P20** · UNIVERSITY OF KANSAS LAWRENCE · 2020 · $139,009

## Abstract

Immunotherapy represents a recent breakthrough in cancer treatment fueled by the accelerating mechanistic 
understanding of how transformed cells subvert our immunosurveillance. Therefore, developing therapeutic 
strategies that enhance systemic immunosurveillance in a controllable manner has become one of the major 
interests in this field. Among different agents, small molecule activators (agonists) of the cGAS-STING 
pathway have recently attracted attention because they are expected to synergize with immunotherapies and 
enhance anti-cancer immune response by upregulating the interferon response. 
We previously identified a compound, BDW568, that was shown to activate the interferon pathway in a 
STING-dependent manner. Surprisingly, follow-up studies demonstrated that cGAS and STING are not direct 
target(s) of BDW568. Therefore, observed phenotype suggests that BDW568 acts either through (1) binding 
to an unknown regulator of the cGAS-STING pathway, or (2) by generating an unknown signaling molecule 
independent of 2’,3’-cGAMP, the endogenous STING agonist. In the proposed study we will identify the 
cellular target of BDW568 responsible for the previously discovered phenotype using two orthogonal 
strategies. In the first approach, we will synthesize BDW568-based photoaffinity probes and use them to 
label any protein that binds to BDW568. Labeled target(s) will be identified by a whole-cell lysate pulldown 
experiments coupled with mass spectrometry (MS). In the second approach, we will use CRISPR-Cas9 to 
individually knock out all the genes that are known to interact with STING or associate with interferon 
pathways. The knockout of the BDW568 target should demonstrate either resistance to the compound or 
elevation of the basal interferon level without BDW568 through STING. Any target candidate that emerges 
from either one of these approaches will be rigorously validated according to the standards of the field to 
establish that observed phenotype is due to on-target engagement. Successful completion of proposed 
studies will expand the target space within cGAS-STING pathway. These insights will lead to additional 
opportunities for developing adjuvant immunotherapies as well as expand our understanding of innate 
immune response in mammalian cells.

## Key facts

- **NIH application ID:** 10242612
- **Project number:** 5P20GM103638-09
- **Recipient organization:** UNIVERSITY OF KANSAS LAWRENCE
- **Principal Investigator:** Jingxin Wang
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $139,009
- **Award type:** 5
- **Project period:** 2012-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242612

## Citation

> US National Institutes of Health, RePORTER application 10242612, Novel target deconvolution in cGAS-STING pathway (5P20GM103638-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10242612. Licensed CC0.

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