CHEMISTRY TOWARDS NOVEL MECHANISM-OF-ACTION COMPOUNDS IN THERAPEUTICS DISCOVERY

Stuart L. Schreiber

Howard Hughes Medical Institute, Harvard University and Broad Institute, Cambridge, MA, USA

Abstract

This presentation will focus on the role of modern asymmetric synthesis in generating 3-D compounds having novel (previously unknown) mechanisms of action (nMoA) in probe and therapeutics discovery. Our hypothesis is that sp3-rich, chiral compounds are especially well suited to bind the topographically complex binding sites of proteins and RNA than traditional, sp2-rich, generally more flat compounds. Improving our ability to access a greater range of binding sites will lead to compounds having novel MoAs, which is key to tackling many problems in biomedical and translational research today. For example, human genetics and biochemical studies of variant proteins can provide a blueprint for the activities that drugs should confer on the more common versions of the proteins, in the context of human physiology and prior to launching a drug-discovery effort, in order to be safe and efficacious. However, the activities suggested by these experiments of nature are challenging and often unfamiliar to the historical path towards drug discovery. For the most part, drugs don’t yet exist that have these suggested MoAs. They demand nMoA compounds. In the area of microbial therapeutics, nMoA compounds are powerful probes of pathogen biology and key to overcoming the general problem of resistance. In this lecture, I will introduce the concept of chemistry driving the discovery of compounds having novel mechanisms of action. After illustrating the synthetic paths we use to create 3-D chiral compounds and their ability to yield nMoA compounds, including most recently as microbial therapeutics, I will describe our efforts to achieve real-time biological annotation of synthetic compounds using thousands of multiplexed measurements of the actions of compounds on cells. If real-time biological annotation of synthetic compounds could become a routine aspect of synthetic organic chemistry in the future, it could provide a means to increase the potential of chemistry to impact biology and medicine.