Zining Wu; Todd L. Graybill; Xin Zeng; Michael Platchek; Jean Zhang; Vera Q. Bodmer; David D. Wisnoski; Jianghe Deng; Frank T. Coppo; Gang Yao; Alex Tamburino; Genaro Scavello; G. Joseph Franklin; Sibongile Mataruse; Katie L. Bedard; Yun Ding; Jing Chai; Jennifer Summerfield; Paolo A. Centrella; Jeffrey A. Messer; Andrew J. Pope; David I. Israel
ACS Comb. Sci., 2015, 17, 12, 722-731
https://doi.org/10.1021/acscombsci.5b00124

Abstract

DNA-encoded small-molecule library technology has recently emerged as a new paradigm for identifying ligands against drug targets. To date, this technology has been used with soluble protein targets that are produced and used in a purified state. Here, we describe a cell-based method for identifying small-molecule ligands from DNA-encoded libraries against integral membrane protein targets. We use this method to identify novel, potent, and specific inhibitors of NK3, a member of the tachykinin family of G-protein coupled receptors (GPCRs). The method is simple and broadly applicable to other GPCRs and integral membrane proteins. We have extended the application of DNA-encoded library technology to membrane-associated targets and demonstrate the feasibility of selecting DNA-tagged, small-molecule ligands from complex combinatorial libraries against targets in a heterogeneous milieu, such as the surface of a cell.