The revolution will be compartmentalized: Miniaturized chemical library synthesis and microfluidic screening technology for distributed drug discovery

The NIH Molecular Libraries Program was founded to translate the discoveries of the Human Genome Project into therapeutics through a network of high-throughput screening centers. A decade of discovery produced hundreds of probes — highly selective small molecules that modulate cellular function — but centralized compound screening bears the same cost and infrastructure burdens of millennial DNA sequencing centers, which has limited access to the technology and, more significantly, the rate of small molecule discovery. We are building a distributable drug discovery platform analogous to next-generation DNA sequencing based on ultra-miniaturized DNA-encoded solid-phase compound libraries and microfluidic instrumentation for scalable, automated screening. I will overview chemical synthesis and microfluidic screening technology development efforts and describe their application in a collaboration with Roche Pharma R&D to discover drug-like ligands of two clinically relevant targets implicated in idiopathic pulmonary fibrosis and several cancers. Looking toward the future, we are exploring approaches that directly translate genomic sequence into bioactive chemical probes toward fulfilling the originally promised pay dirt of the Human Genome Project.