An Enzyme-Directed Imidazoquinoline Activated by Drug Resistance.

Drug efflux and enzymatic drug degradation are two cellular mechanisms that contribute to drug resistance in many cancers. Herein, we report the synthesis and in vitro activity of a pro-immunostimulant that exploits both processes in tandem to selectively confer cancer-mediated immunogenicity. We demonstrate that an imidazoquinoline pro-immunostimulant is inactive until it is selectively metabolized to an active immunostimulant by an endogenous α-mannosidase enzyme expressed within multidrug-resistant cancer cells. Following conversion, the immunostimulant is transported to the extracellular space via drug efflux, resulting in the activation of model bystander immune cells. Taken together, these results suggest that enzyme-directed immunostimulants can couple immunogenicity to these mechanisms of drug resistance. We name this process bystander-assisted immunotherapy, and envision that it could be advanced to treat drug-resistant diseases that rely on enzymatic degradation or drug efflux to persist.

Synthetic agonists of NOD-like, RIG-I-like, and C-type lectin receptors for probing the inflammatory immune response.

Synthetic agonists of innate immune cells are of interest to immunologists due to their synthesis from well-defined materials, optimized activity, and monodisperse chemical purity. These molecules are used in both prophylactic and therapeutic contexts from vaccines to cancer immunotherapies. In this review we highlight synthetic agonists that activate innate immune cells through three classes of pattern recognition receptors: NOD-like receptors, RIG-I-like receptors, and C-type lectin receptors. We classify these agonists by the receptor they activate and present them from a chemical perspective, focusing on structural components that define agonist activity. We anticipate this review will be useful to the medicinal chemist as a guide to chemical motifs that activate each receptor, ultimately illuminating a chemical space ripe for exploration.

An Enzyme-Directed Imidazoquinoline for Cancer Immunotherapy.

Herein we report the synthesis and activity of an enzyme-directed immunostimulant with immune cell activation mediated by ß-galactosidase, either exogenously added, or on B16 melanoma cells. Covalent attachment of a ß-galactopyranoside to an imidazoquinoline immunostimulant at a position critical for activity resulted in a pro-immunostimulant that could be selectively converted by ß-galactosidase into an active immunostimulant. The pro-immunostimulant exhibited ß-galactosidase-directed immune cell activation as measured by NF-κB transcription in RAW-Blue macrophages or cytokine production (TNF, IL-6, IL-12) in JAWSII monocytes. Conversion of the pro-immunostimulant into an active immunostimulant was also found to occur using ß-galactosidase-enriched B16 melanoma cells. In co-culture experiments with either immune cell line, ß-galactosidase-enriched B16 cells effected activation of bystander immune cells.