Molecule That Activate Natural Immune Boosting Protein Called STING
Scientists at Scripps Research have discovered a molecule which will activate a natural immune-boosting protein called STING. The findings mark a key advance within the field of oncology, because the STING protein is understood for its strong antitumor properties.
STING (Short for Stimulator of Interferon Genes) marshals the immune system against viral & cancerous invaders &, due to its role in promoting antitumor immunity, has garnered enthusiastic interest from drug developers.
However, STING natural activators within the body are unstable DNA-related molecules that don’t last long within the bloodstream. That has hindered the development of treatments based on them, and has prompted an search for a hardier STING activating small molecule — one which will circulate within the blood and work against tumors “systemically”, wherever they’ll exist within the body.
The Scripps Research scientists, who report their finding in Science on Aug 20, screened a group of suitable small molecules with diverse structures and identified several that activate STING. After modifying one among these molecules to optimize its properties, they found that delivering it systemically into mice with an injection greatly reduced the expansion of an aggressive form of melanoma.
The discovery raises the likelihood of a circulating drug that would activate STING and suppress a good range of cancers.
“A systemic STING-activating molecule could have considerable utility, & not only as a therapeutic for cancer & communicable disease , but also as a search for studying STING-dependent antitumor immunity and a number of other STING-related biological processes,” says co-senior author Luke Lairson, PhD, Professor within the Department of Chemistry at Scripps Research.
Lairson and colleagues found that their optimized STING-activator, which they named SR-717, appears to activate the STING protein within the same way as its natural activators within the body. Using X-ray crystallography to image the interaction at atomic scale, they showed that both SR-717 and a known natural activator bind to an equivalent site on STING and induce an equivalent shape-change within the protein.
In an animal model of aggressive melanoma, SR-717 dramatically suppressed tumor growth, prevented metastasis, induced the presentation of tumor molecules to the system , and robustly boosted levels around tumors of CD8+ T cells & NK cells — both of which are known to be among the immune system heaviest antitumor weapons. At this effective dose, there was no evidence of serious adverse side effects on the animals.
Lairson and colleagues are continuing to review SR-717, with the hope of developing it into a new latest anticancer treatment that would be used alone or together with other treatments.
The work was a collaboration of Lairson’s lab, the lab of John Teijaro, PhD, Professor within the Department of Immunology and Microbiology at Scripps Research, and therefore the lab of Mike Petrassi, PhD, vice chairman of Medicinal Chemistry at Scripps Research drug development Arm, Calibr. The project was led by first author Emily Chin, PhD, a staff scientist within the Lairson lab, with Vincent Vartabedian & Ying Jia conducting the in vivo characterization of SR-717, and Chenguang Yu, PhD, leading the medicinal chemistry efforts.
“Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic” was written by Emily Chin, Chenguang Yu, Vincent Vartabedian, Ying Jia, Manoj Kumar, Ana Maria Gamo Albero, William Vernier, Sabrina Ali, Mildred Kissai, Daniel Lazar, Nhan Nguyen, Laura Pereira, Brent Benish, Ashley Woods, Sean Joseph, Alan Chu, Kristen Johnson, Philipp Sander, Francisco Martinez-Pena, Eric Hampton, Travis Young, Dennis Wolan, Arnab Chatterjee, Peter Schultz, Michael Petrassi, John Teijaro, and Luke Lairson, all of Scripps Research during the study.