Canham, Steve and Feng, Yan (2023) Activation of human STING by a molecular glue-like compound. Nature chemical biology. ISSN 1552-4469; 1552-4450

Abstract

Stimulator of interferon genes (STING) is a dimeric transmembrane adaptor protein that plays an important role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand cGAMP to the cytosolic ligand-binding domain or binding of an artificial compound, C53, to a transmembrane domain pocket. Here we report the discovery through functional screens of a new class of compounds, named NVS-STGs, that activate human STING using an alternative mechanism. Our cryo-electron microscopic (Cryo-EM) structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models. These findings establish a distinct class of agonists that can act synergistically with both cGAMP and C53 in activating STING for cancer therapy.

Item Type:	Article
Keywords:	Immunooncology, STING, Innate Immunology
Date Deposited:	27 Oct 2023 00:45
Last Modified:	27 Oct 2023 00:45
URI:	https://oak.novartis.com/id/eprint/49281