2. Academic Validation
  3. Development of Highly Potent, Selective, and Cellular Active Triazolo[1,5- a]pyrimidine-Based Inhibitors Targeting the DCN1-UBC12 Protein-Protein Interaction

Development of Highly Potent, Selective, and Cellular Active Triazolo[1,5- a]pyrimidine-Based Inhibitors Targeting the DCN1-UBC12 Protein-Protein Interaction

  • J Med Chem. 2019 Mar 14;62(5):2772-2797. doi: 10.1021/acs.jmedchem.9b00113.
Shuai Wang 1 2 3,  Lijie Zhao 1 2 3,  Xiao-Jing Shi 1 2 3,  Lina Ding 1 2 3,  Linlin Yang 4,  Zhi-Zheng Wang 1 2 3,  Dandan Shen 1 2 3,  Kai Tang 1 2 3,  Xiao-Jing Li 1 2 3,  Maa Mamun 1 2 3,  Huiju Li 1 2 3,  Bin Yu 1 2 3 5,  Yi-Chao Zheng 1 2 3,  Shaomeng Wang 1 6,  Hong-Min Liu 1 2 3
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences and Institute of Drug Discovery & Development , Zhengzhou University , Zhengzhou 450001 , China.
  • 2 Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety , Zhengzhou 450001 , China.
  • 3 Key Laboratory of Advanced Technology of Drug Preparation Technologies, Zhengzhou University, Ministry of Education of China, Zhengzhou 450001 , China.
  • 4 Department of Pharmacology, School of Basic Medical Sciences , Zhengzhou University , Zhengzhou 450001 , China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology , Nanjing University , Nanjing 210023 , Jiangsu , People's Republic of China.
  • 6 Departments of Internal Medicine, Pharmacology, Medicinal Chemistry , University of Michigan , 1600 Huron Parkway , Ann Arbor , Michigan 48109 , United States.
PMID: 30803229 DOI: 10.1021/acs.jmedchem.9b00113
Abstract

The cullin-RING ubiquitin ligases (CRLs) are responsible for about 20% of cellular protein degradation and regulate diverse cellular processes, and the dysfunction of CRLs is implicated in human diseases. Targeting the CRLs has become an emerging strategy for the treatment of human diseases. Herein, we describe the discovery of a hit compound from our in-house library and further structure-based optimizations, which have enabled the identification of new triazolo[1,5- a]pyrimidine-based inhibitors targeting the DCN1-UBC12 interaction. Compound WS-383 blocks the DCN1-UBC12 interaction (IC50 = 11 nM) reversibly and shows selectivity over selected kinases. WS-383 exhibits cellular target engagement to DCN1 in MGC-803 cells. WS-383 inhibits Cul3/1 neddylation selectively over other cullins and also induces accumulation of p21, p27, and NRF2. Collectively, targeting the DCN1-UBC12 interaction would be a viable strategy for selective neddylation inhibition of Cul3/1 and may be of therapeutic potential for disease treatment in which Cul3/1 is dysregulated.

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