Pei-Pei Kung; Patrick Bingham; Benjamin J. Burke; Qiuxia Chen; Xuemin Cheng; Ya-Li Deng; Dengfeng Dou; Junli Feng; Gary M. Gallego; Michael R. Gehring; Stephan K. Grant; Samantha Greasley; Anthony R. Harris; Karen A. Maegley; Jordan Meier; Xiaoyun Meng; Jose L. Montano; Barry A. Morgan; Brigitte S. Naughton; Prakash B. Palde; Thomas A. Paul; Paul Richardson; Sylvie Sakata; Alex Shaginian; William K. Sonnenburg; Chakrapani Subramanyam; Sergei Timofeevski; Jinqiao Wan; Wen Yan; Albert E. Stewart
ACS Med. Chem. Lett., 2020, 11(6), 1175-1184
https://doi.org/10.1021/acsmedchemlett.0c00029

Abstract

Two novel compounds were identified as Naa50 binders/inhibitors using DNA-encoded technology screening. Biophysical and biochemical data as well as co-crystal structures were obtained for both compounds (3a and 4a) to understand their mechanism of action. These data were also used to rationalize the binding affinity differences observed between the two compounds and a MLGP peptide-containing substrate. Cellular target engagement experiments further confirm the Naa50 binding of 4a and demonstrate its selectivity toward related enzymes (Naa10 and Naa60). Additional analogs of inhibitor 4a were also evaluated to study the binding mode observed in the co-crystal structures.