대표연구 논문 실적
Discovery of a New Tetrahydroquinoline-Based Chemotype for STING Inhibition with In Vivo Efficacy against Acute Kidney Injury
발행년도
Early Access
저자
So Hyeon Jeong, Ji Hun Wi, Jiyoon Park, Yeseul Kim, Jinhee Mun, Hayeon Kim, Joo-Youn Lee, Soyoung Yoon, Hankum Park, Gyu Yong Song, Cheulhee Jung, Sanghee Lee, and Hyejin Kim
저널
JOURNAL OF MEDICINAL CHEMISTRY
Author
admsnulamp
Date
2026-05-18
Views
89
Abstract
Aberrant activation of the stimulator of interferon genes (STING) drives excessive type I interferon and inflammatory responses implicated in autoimmune and inflammatory diseases, including acute kidney injury (AKI). Here, we report the discovery of a tetrahydroquinoline-based STING inhibitor chemotype, represented by KSI-028, that expands the limited scaffold diversity of current small-molecule STING inhibitors. Mechanistic studies suggest that KSI-028 engages STING through a noncanonical, likely allosteric, binding mode with sustained target engagement. KSI-028 potently suppressed STING-dependent signaling and reduced type I interferon and pro-inflammatory cytokine production in both murine and human cells. In a cisplatin-induced AKI mouse model, KSI-028 attenuated renal and hepatic injury and down-regulated STING-associated inflammatory gene expression. These findings establish the tetrahydroquinoline scaffold as a promising foundation for the development of next-generation STING inhibitors with alternative target engagement modes for the treatment of STING-driven inflammatory disorders.
DOI: http://dx.doi.org/10.1021/acs.jmedchem.6c00162
Aberrant activation of the stimulator of interferon genes (STING) drives excessive type I interferon and inflammatory responses implicated in autoimmune and inflammatory diseases, including acute kidney injury (AKI). Here, we report the discovery of a tetrahydroquinoline-based STING inhibitor chemotype, represented by KSI-028, that expands the limited scaffold diversity of current small-molecule STING inhibitors. Mechanistic studies suggest that KSI-028 engages STING through a noncanonical, likely allosteric, binding mode with sustained target engagement. KSI-028 potently suppressed STING-dependent signaling and reduced type I interferon and pro-inflammatory cytokine production in both murine and human cells. In a cisplatin-induced AKI mouse model, KSI-028 attenuated renal and hepatic injury and down-regulated STING-associated inflammatory gene expression. These findings establish the tetrahydroquinoline scaffold as a promising foundation for the development of next-generation STING inhibitors with alternative target engagement modes for the treatment of STING-driven inflammatory disorders.
DOI: http://dx.doi.org/10.1021/acs.jmedchem.6c00162
