STING-activating molecule fights tumors via systemic delivery

Drugmakers have been buzzing about the stimulator of interferon genes, or STING, protein because of its potential to boost the activity of immunotherapy cancer drugs. To date, compounds designed to target STING have been effective only when they’re injected directly into tumors. Scientists at GlaxoSmithKline now report a diamidobenzimidazole molecule (shown) that activates STING and fights tumors in mice when given via intravenous injection (Nature 2018, DOI: 10.1038/s41586-018-0705-y). The researchers, led by Joshi Ramanjulu, initially identified an amidobenzimidazole compound that bound to STING. STING forms a homodimer, made of two identical proteins. When the GSK researchers examined the crystal structure of the two interacting, they found two molecules of the amidobenzimidazole bound to the STING homodimer in proximity. Inspired by this symmetrical structure, they covalently linked two of the compounds with a four-carbon chain, creating a diamidobenzimidazole. This molecule bound to STING 1,000 times more strongly than the unlinked solo compound. They then optimized the structure to make a more potent molecule, which prevented tumors from growing in mice when given systemically by injection.