Johnny Bennett

From the Sublime to the Ridiculously Difficult – A Medicinal Chemist’s Tale

“Cyclic Dinucleotide STING Agonists for Immuno-Oncology”

Pharmacological activation of innate immune, danger-sensing pathways has recently emerged as a promising strategy for enhancing cancer immunotherapy. In particular, agonists of the Stimulator of Interferon Genes (STING) protein have demonstrated robust efficacy in syngeneic mouse tumor models via apparent generation of innate and adaptive anti-tumor immune responses as well as tumor-specific immune memory. The identification of an endogenous cyclic dinucleotide (CDN) agonist of human STING, 2’,3’-cGAMP, has spurred interest in discovery of novel CDNs suitable for clinical investigation in cancer patients.

This presentation will detail efforts at MSD to elucidate structure-activity relationships in a synthetically complex cyclic dinucleotide structural class. Optimization of total synthesis routes to novel CDNs along with implementation of new synthetic and biocatalytic strategies has enabled a survey of previously unexplored CDN scaffold modifications. Computational and biostructural methods have been applied to influence design of novel STING agonists. This work has resulted in the invention of a variety of potent, selective STING agonists.

Characterization of select molecules in mouse tumor models will be presented, including evidence of impressive anti-tumor effects in both single-agent treatment and combination treatment with an anti-PD1 antibody. In addition, we have demonstrated evidence for induction of anti-tumor immune memory in mouse models and have generated translational data in human tumor samples supporting advancement of STING agonists to the clinic.