Discovery

NIH backs UT Southwestern push to drug STING in autoimmune disease

Edited by Robert McTiernan··2 min read
NIH backs UT Southwestern push to drug STING in autoimmune disease

UT Southwestern Medical Center has received a USD 2.57 million NIH award from the National Institute of Allergy and Infectious Diseases (NIAID) to support a multi-project research program developing small-molecule antagonists of the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway for autoimmune and inflammatory diseases.

The P01 Program Project grant supports four interrelated projects led by six principal investigators — Yonghao Yu, Nan Yan, Xiaochen Bai, Noelle Sevilir Williams, Chuo Chen, and Xuewu Zhang — spanning immunology, structural biology, medicinal chemistry, proteomics, and pharmacology. The project period runs through June 2031, with the current budget period ending in June 2027.

The cGAS-STING pathway senses cytosolic DNA and triggers innate immune responses, including type I interferon signaling. Aberrant pathway activation has been implicated in monogenic interferonopathies including Aicardi-Goutières syndrome and STING-associated vasculopathy with onset in infancy (SAVI), as well as broader autoimmune diseases including systemic lupus erythematosus. The researchers aim to identify new ways of pharmacologically suppressing STING while defining the downstream signaling mechanisms involved in pathological inflammation.

Direct STING inhibition remains an early-stage drug-discovery field despite years of genetic and preclinical evidence linking pathway hyperactivation to autoimmune and autoinflammatory disease. Small-molecule antagonists including H-151 and SN-011 have demonstrated activity in preclinical disease models, but direct STING inhibitors have yet to establish clinical proof of concept. Species-specific pharmacology, compound selectivity, and the potential consequences of chronically suppressing an antiviral innate immune pathway remain development challenges.

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The four projects combine disease models with complementary drug-discovery approaches. Project 1 will test how STING antagonists suppress inflammation in genetic and pathological mouse models, while Project 2 will use structural methods to determine how small-molecule ligands alter STING conformation and function. Project 3 will use those structural insights to develop antagonists with distinct binding modes.

Project 4 will apply an affinity-based chemoproteomic technology to identify additional STING-reactive compounds, potentially expanding the chemical space available for direct inhibition beyond established antagonist scaffolds. A shared scientific core will provide cryo-electron microscopy infrastructure across the program.

The program is therefore focused less on establishing STING's role in inflammatory disease than on addressing the chemistry and pharmacology that have limited translation of the target into therapeutics. The combination of structural studies, chemoproteomic screening, medicinal chemistry, and disease-model validation is intended to generate pharmacological tools and candidate antagonists capable of testing direct STING inhibition more rigorously.

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