9PPL

Structure of STING in complex with MK-2118

This is a non-PDB format compatible entry.

Summary for 9PPL

• Entry DOI: 10.2210/pdb9ppl/pdb
• Descriptor: Stimulator of interferon genes protein, (2S)-4-(5,6-dimethoxy-1-benzothiophen-2-yl)-2-methyl-4-oxobutanoic acid (3 entities in total)
• Functional Keywords: sting, mk-2118, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 21863.54

Authors

Lesburg, C.A.,Henderson, T.,Ho, T.,Hayes, R.P.,Bennett, J. (deposition date: 2025-07-21, release date: 2026-07-01, Last modification date: 2026-07-29)

Primary citation

Henderson, T.,Altman, M.D.,Buevich, A.V.,Cash, B.,Cemerski, S.,Chang, W.,Chen, Y.,Childers, M.,Cumming, J.,Dandliker, P.J.,Feng, G.,Haidle, A.,Hayes, R.P.,Ho, T.,Jewell, J.P.,Kariv, I.,Knemeyer, I.,Kopinja, J.,Lacey, B.M.,Laskey, J.,Lesburg, C.A.,Liang, R.,Lim, J.,Long, B.J.,Lu, M.,Ma, Y.,Minnihan, E.C.,Otte, R.D.,O'Donnell, G.,Pan, B.S.,Perera, S.A.,Piesvaux, J.A.,Presland, J.P.,Price, L.,Rakhilina, L.,Sauvagnat, B.,Schroeder, G.K.,Sharma, S.,Trotter, B.W.,Tyagarajan, S.,Woo, H.,Wyss, D.F.,Xu, S.,Addona, G.H.,Bennett, D.J.
Discovery of MK-2118, a Small-Molecule Agonist of STING.
Acs Med.Chem.Lett., 17:1501-1507, 2026

PubMed Abstract: Agonists of Stimulator of Interferon Genes (STING) have the potential to activate the innate and adaptive immune system for cancer treatment. Early efforts in identifying suitable therapeutics were focused on cyclic dinucleotide (CDN) analogs of 2',3'-cGAMP, the endogenous ligand to STING. CDNs lack of tractable bioavailability led us to consider small-molecule modulators of STING. We previously reported the identification of MSA-2, an orally available non-nucleotide STING agonist with antitumor activity. Optimization efforts in this series faced challenges with uniform activity across species, cell shift, and steep structure activity relationships. Herein we report lead optimization efforts guided by structure-based drug design to identify the MSA-2 analog MK-2118.

PubMed: 42445025
DOI: 10.1021/acsmedchemlett.5c00540

Experimental method

X-RAY DIFFRACTION (2.01 Å)