Kung Pei-Pei, Bingham Patrick, Burke Benjamin J, Chen Qiuxia, Cheng Xuemin, Deng Ya-Li, Dou Dengfeng, Feng Junli, Gallego Gary M, Gehring Michael R, Grant Stephan K, Greasley Samantha, Harris Anthony R, Maegley Karen A, Meier Jordan, Meng Xiaoyun, Montano Jose L, Morgan Barry A, Naughton Brigitte S, Palde Prakash B, Paul Thomas A, Richardson Paul, Sakata Sylvie, Shaginian Alex, Sonnenburg William K, Subramanyam Chakrapani, Timofeevski Sergei, Wan Jinqiao, Yan Wen, Stewart Albert E
Worldwide Research and Development, Pfizer Inc., 10770 Science Center Drive, San Diego, California 92121, United States.
HitGen Inc., Building 6, No.8, Huigu first East Road, Tianfu International Bio-Town, Shuangliu District, Chengdu, Sichuan 610200, P.R. China.
ACS Med Chem Lett. 2020 Apr 10;11(6):1175-1184. doi: 10.1021/acsmedchemlett.0c00029. eCollection 2020 Jun 11.
Two novel compounds were identified as Naa50 binders/inhibitors using DNA-encoded technology screening. Biophysical and biochemical data as well as cocrystal structures were obtained for both compounds ( and ) 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 and demonstrate its selectivity toward related enzymes (Naa10 and Naa60). Additional analogs of inhibitor were also evaluated to study the binding mode observed in the cocrystal structures.
使用DNA编码技术筛选鉴定出两种新型化合物作为Naa50结合剂/抑制剂。获得了这两种化合物（和）的生物物理和生化数据以及共晶体结构，以了解它们的作用机制。这些数据还用于解释两种化合物与含MLGP肽的底物之间观察到的结合亲和力差异。细胞靶点结合实验进一步证实了与Naa50的结合，并证明了其对相关酶（Naa10和Naa60）的选择性。还评估了抑制剂的其他类似物，以研究在共晶体结构中观察到的结合模式。
