Structural Evaluations of a Selective Human STINGA230 Agonist and Its Use in Macrophage Immunotherapies

Zhichao Tang; Junxing Zhao; Ying Li; Shallu Tomer; Manikandan Selvaraju; Nicholas Tien; Diyun Sun; David K Johnson; Anjie Zhen; Pingwei Li; Jingxin Wang

doi:10.1021/acsmedchemlett.4c00048

Structural Evaluations of a Selective Human STING^A230 Agonist and Its Use in Macrophage Immunotherapies

ACS Med Chem Lett. 2024 Apr 12;15(5):653-658. doi: 10.1021/acsmedchemlett.4c00048. eCollection 2024 May 9.

Authors

Affiliations

¹ Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States.
² Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, United States.
³ Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, United States.
⁴ Computation Chemical Biology Core and Molecular Graphics and Modeling Laboratory, University of Kansas, Lawrence, Kansas 66047, United States.

PMID: 38746895
PMCID: PMC11089548 (available on 2025-05-09)
DOI: 10.1021/acsmedchemlett.4c00048

Abstract

Previously we identified a non-nucleotide agonist BDW568 that selectively activates the human STING^A230 allele. Here, we further characterized the mechanism of BDW568 and highlighted its potential use for selectively controlling the activation of engineered macrophages that constitutively express STING^A230 as a genetic adjuvant. We obtained the crystal structure of the C-terminal domain of STING^A230 complexed with BDW-OH (active metabolite) at 1.95 Å resolution. Structure-activity relationship studies revealed that all three heterocycles in BDW568 and the S-acetate side chain are critical for retaining activity. We demonstrated that BDW568 could robustly activate type I interferon signaling in purified human primary macrophages that were transduced with lentivirus expressing STING^A230. In contrast, BDW568 could not stimulate innate immune responses in human primary peripheral blood mononuclear cells in healthy donors in the absence of a STING^A230 allele. This high STING variant specificity suggested a promising application of STING^A230 agonists in macrophage-based therapeutic approaches.