Svetlana L. Belyanskaya; Yun Ding; James Callahan; Aili Lazaar; David I. Israel
ChemBioChem, 2017, 18(9), 837-842
https://doi.org/10.1002/cbic.201700014

Abstract

We describe the development of a DNA‐encoded small‐molecule technology platform, and its use in discovering the soluble epoxide hydrolase (sEH) inhibitor GSK2256294. This molecule progressed through preclinical development and entered a human clinical trial where it was found to be orally bioavailable and well tolerated, demonstrating potent and dose‐dependent inhibition of sEH.
Abstract
DNA-encoded chemical library technology was developed with the vision of its becoming a transformational platform for drug discovery. The hope was that a new paradigm for the discovery of low-molecular-weight drugs would be enabled by combining the vast molecular diversity achievable with combinatorial chemistry, the information-encoding attributes of DNA, the power of molecular biology, and a streamlined selection-based discovery process. Here, we describe the discovery and early clinical development of GSK2256294, an inhibitor of soluble epoxide hydrolase (sEH, EPHX2), by using encoded-library technology (ELT). GSK2256294 is an orally bioavailable, potent and selective inhibitor of sEH that has a long half life and produced no serious adverse events in a first-time-in-human clinical study. To our knowledge, GSK2256294 is the first molecule discovered from this technology to enter human clinical testing and represents a realization of the vision that DNA-encoded chemical library technology can efficiently yield molecules with favorable properties that can be readily progressed into high-quality drugs.