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Discovering Drugs with DNA‐Encoded Library Technology: From Concept to Clinic with an Inhibitor of Soluble Epoxide Hydrolase
Author(s) -
Belyanskaya Svetlana L.,
Ding Yun,
Callahan James F.,
Lazaar Aili L.,
Israel David I.
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700014
Subject(s) - drug discovery , epoxide hydrolase 2 , computational biology , dna , small molecule , chemistry , combinatorial chemistry , biology , biochemistry , enzyme
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.