Discovering Drugs with DNA-Encoded Library Technology: From Concept to Clinic with an Inhibitor of Soluble Epoxide Hydrolase
Discovering Drugs with DNA-Encoded Library Technology: From Concept to Clinic with an Inhibitor of Soluble Epoxide Hydrolase
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DOI：
10.1002/cbic.201700014
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发表时间：
2017-05-04
期刊：
影响因子：
3.2
通讯作者：
Israel, David I.
中科院分区：
文献类型：
--
作者：
Belyanskaya, Svetlana L.;Ding, Yun;Israel, David I.
DNA 编码化学库技术的开发愿景是成为药物发现的变革平台。人们希望，通过将组合化学可实现的巨大分子多样性、DNA 的信息编码属性、分子生物学的力量以及简化的基于选择的发现过程相结合，可以实现低分子量药物发现的新范式。在这里，我们描述了利用编码文库技术 (ELT) 发现和早期临床开发可溶性环氧化物水解酶 (sEH、EPHX2) 抑制剂 GSK2256294。 GSK2256294 是一种口服生物可利用的、有效的、选择性的 sEH 抑制剂，半衰期长，并且在首次人体临床研究中没有产生严重的不良事件。据我们所知，GSK2256294是通过该技术发现的第一个进入人体临床测试的分子，代表了DNA编码化学库技术可以有效产生具有良好特性的分子，并可以轻松地转化为高质量药物的愿景的实现。
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.