Molecular Glues Inspired by Natural Products As Novel Chemical Probes and Drug Leads

Natural products have served as an invaluable source of both drugs and chemical tools to explore a variety of biological processes for chemical biologists. Rapamycin, FK506 and cyclosporin A (CsA) are macrocycles that have played important roles in unraveling cellular pathways and treatments of organ transplants, cancer and other diseases. These macrocycles have a unique and extraordinary mode of action—they work by serving as molecular glues to bring two cellular proteins together to achieve the inhibition of their respective, ultimate targets, the protein phosphatase calcineurin (CsA and FK506) and mTOR (rapamycin). Inspired by the mode of action of these natural products and their intrinsic drug-like properties, we embarked on the design and synthesis of a novel class of hybrid macrocycles known as rapafucins by replacing the mTOR-interacting effector domain of rapamycin with a combinatorial oligopeptide library. The first generation, 45,000-compound rapafucin library has been synthesized and screened in a number of cell- and target-based assays. Hits against a wide variety of protein targets, particularly those considered undruggable, have been identified and characterized.