Timothy Henderson*, Michael D. Altman, Alexei V. Buevich, Brandon Cash, Saso Cemerski, Wonsuk Chang, Yiping Chen, Matthew Childers, Jared Cumming, Peter J. Dandliker, Guo Feng, Andrew Haidle, Robert P. Hayes, Thu Ho, James P. Jewell, Ilona Kariv, Ian Knemeyer, Johnny Kopinja, Brian M. Lacey, Jason Laskey, Charles A. Lesburg, Rui Liang, Jongwon Lim, Brian J. Long, Min Lu, Yanhong Ma, Ellen C. Minnihan, Ryan D. Otte, Gregory O’Donnell, Bo-Sheng Pan, Samanthi A. Perera, Jennifer A. Piesvaux, Jeremy P. Presland, Laura Price, Larissa Rakhilina, Berengere Sauvagnat, Gottfried K. Schroeder, Sharad Sharma, B. Wesley Trotter, Sriram Tyagarajan, Hyun Woo, Daniel F. Wyss, Serena Xu, George H. Addona and David Jonathan Bennett,
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Discovery of MK-2118, a Small-Molecule Agonist of STING
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.
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ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics)
Biological characterization of new molecular entities in the context of drug discovery
Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc.
Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry
Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources
Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response
Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic
Mechanistic drug metabolism and regulation of metabolic enzyme gene expression
Chemistry patents relevant to the medicinal chemistry field.
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