Macrocycles are found widely in nature and several of these natural products are marketed as effective drugs with good drug-like properties. Synthetic macrocycles by contrast have been generally underexploited for drug discovery. Ensemble Therapeutics has developed a DNA-programmed chemistry platform for the rapid synthesis and screening of macrocycles (EnsemblinsTM). IL17A has been demonstrated to be a key pro-inflammatory cytokine in human rheumatoid arthritis and in several rodent models of arthritis. Small molecule macrocyclic compounds have been discovered that are nanomolar inhibitors of the interaction of the IL17A cytokine with its receptor. These compounds act as inhibitors of IL17A-stimulated IL-6 production in RASF and HT29 cells, and are also anti-inflammatory in an IL17-directed murine delayed-type hypersensitivity model. Unlike the IL17 biological therapies currently in clinical development, Ensemblins can be optimized to have desirable drug-like properties including membrane permeability and oral bioavailability.

Macrocycles for drug discovery: Identification of small molecule synthetic macrocycle antagonists of human IL17A

245th National Meeting (2013)

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