Discovery of MK-1454: A Potent Cyclic Dinucleotide Stimulator of Interferon Genes Agonist for the Treatment of Cancer
Wonsuk Chang, Michael D. Altman, Charles A. Lesburg, Samanthi A. Perera, Jennifer Piesvaux, Gottfried K. Schroeder, Daniel F. Wyss, Sašo Čemerski, Yiping Chen, Edward DiNunzio, Andrew M. Haidle, Thu Ho, Ilona Kariv, Ian Knemeyer, Johnny E. Kopinja, Brian M. Lacey, Jason Laskey, Jongwon Lim, Brian J. Long, Yanhong Ma, Matthew L. Maddess, Bo‐Sheng Pan, Jeremy Presland, E. T. C. Spooner, Dietrich Steinhuebel, Quang Truong, Zhibo Zhang, Jianmin Fu, George H. Addona, Alan B. Northrup, Emma R. Parmee, James R. Tata, David Jonathan Bennett, Jared N. Cumming, Tony Siu, B. Wesley Trotter
Abstract
Stereochemically and structurally complex cyclic dinucleotide-based stimulator of interferon genes (STING) agonists were designed and synthesized to access a previously unexplored chemical space. The assessment of biochemical affinity and cellular potency, along with computational, structural, and biophysical characterization, was applied to influence the design and optimization of novel STING agonists, resulting in the discovery of MK-1454 as a molecule with appropriate properties for clinical development. When administered intratumorally to immune-competent mice-bearing syngeneic tumors, MK-1454 exhibited robust tumor cytokine upregulation and effective antitumor activity. Tumor shrinkage in mouse models that are intrinsically resistant to single-agent therapy was further enhanced when treating the animals with MK-1454 in combination with a fully murinized antimouse PD-1 antibody, mDX400. These data support the development of STING agonists in combination with pembrolizumab (humanized anti-PD-1 antibody) for patients with tumors that are partially responsive or nonresponsive to single-agent anti-PD-1 therapy.