8STI

human STING with agonist XMT-1616

Summary for 8STI

• Entry DOI: 10.2210/pdb8sti/pdb
• Descriptor: Stimulator of interferon genes protein, 3-[(2E)-4-{5-carbamoyl-2-[(4-ethyl-2-methyl-1,3-oxazole-5-carbonyl)amino]-7-(3-hydroxypropoxy)-1H-benzimidazol-1-yl}but-2-en-1-yl]-2-[(4-ethyl-2-methyl-1,3-oxazole-5-carbonyl)amino]-3H-imidazo[4,5-b]pyridine-6-carboxamide (3 entities in total)
• Functional Keywords: agonist, sting, immune system, immune system-agonist complex, immune system/agonist
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 22242.92

Authors

Duvall, J.R.,Bukhalid, R.A. (deposition date: 2023-05-10, release date: 2023-07-26, Last modification date: 2023-08-16)

Primary citation

Duvall, J.R.,Thomas, J.D.,Bukhalid, R.A.,Catcott, K.C.,Bentley, K.W.,Collins, S.D.,Eitas, T.,Jones, B.D.,Kelleher, E.W.,Lancaster, K.,Protopopova, M.,Ray, S.S.,Ter-Ovanesyan, E.,Xu, L.,Yang, L.,Zurita, J.,Damelin, M.,Toader, D.,Lowinger, T.B.
Discovery and Optimization of a STING Agonist Platform for Application in Antibody Drug Conjugates.
J.Med.Chem., 66:10715-10733, 2023

PubMed Abstract: While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody-drug conjugate (ADC) could overcome current limitations by improving tumor accessibility, allowing for systemic administration as well as tumor-localized activation of STING for greater anti-tumor activity and better tolerability. In line with this effort, a STING agonist ADC platform was identified through systematic optimization of the payload, linker, and scaffold based on multiple factors including potency and specificity in both in vitro and in vivo evaluations. The platform employs a potent non-cyclic dinucleotide STING agonist, a cleavable ester-based linker, and a hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built with the resulting STING agonist platform induced robust and durable anti-tumor activity and demonstrated high stability and favorable pharmacokinetics in nonclinical species.

PubMed: 37486969
DOI: 10.1021/acs.jmedchem.3c00907

Experimental method

X-RAY DIFFRACTION (1.72 Å)