2. Academic Validation
  3. Characterization of Specific N-α-Acetyltransferase 50 (Naa50) Inhibitors Identified Using a DNA Encoded Library

Characterization of Specific N-α-Acetyltransferase 50 (Naa50) Inhibitors Identified Using a DNA Encoded Library

  • ACS Med Chem Lett. 2020 Apr 10;11(6):1175-1184. doi: 10.1021/acsmedchemlett.0c00029.
Pei-Pei Kung 1,  Patrick Bingham 1,  Benjamin J Burke 1,  Qiuxia Chen 2,  Xuemin Cheng 2,  Ya-Li Deng 1,  Dengfeng Dou 2,  Junli Feng 1,  Gary M Gallego 1,  Michael R Gehring 1,  Stephan K Grant 1,  Samantha Greasley 1,  Anthony R Harris 1,  Karen A Maegley 1,  Jordan Meier 3,  Xiaoyun Meng 2,  Jose L Montano 3,  Barry A Morgan 4 2,  Brigitte S Naughton 1,  Prakash B Palde 1,  Thomas A Paul 1,  Paul Richardson 1,  Sylvie Sakata 1,  Alex Shaginian 2,  William K Sonnenburg 2,  Chakrapani Subramanyam 1,  Sergei Timofeevski 1,  Jinqiao Wan 2,  Wen Yan 1,  Albert E Stewart 1
Affiliations

Affiliations

  • 1 Worldwide Research and Development, Pfizer Inc., 10770 Science Center Drive, San Diego, California 92121, United States.
  • 2 HitGen Inc., Building 6, No.8, Huigu first East Road, Tianfu International Bio-Town, Shuangliu District, Chengdu, Sichuan 610200, P.R. China.
  • 3 Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland 21702, United States.
  • 4 HitGen Pharmaceuticals Inc., PO Box 88240, Houston, Texas 77288, United States.
PMID: 32550998 DOI: 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 cocrystal 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 cocrystal structures.

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