N-terminal acetylation is an abundant modification influencing protein functions, and 80% of mammalian cytosolic proteins are acetylated in this manner, so it could be an untapped small molecule target. Researchers at St. Jude and other institutions collaborated to develop chemical probes that target N-terminal acetylation dependent interaction between an E2 conjugating enzyme and DCN1. The inhibitors are highly selective with respect to other protein acetyl-amide-binding sites, inhibit NEDD8 ligation in vitro and in cells, and suppress anchorage-independent growth of a cell line with DCN1 amplification, and so the researchers have demonstrated these to be druggable targets and have insights into targeting E2-E3 ligases.
The Researches sought to determine whether chemical disruption of a protein-protein interaction controlled by this modification might be useful for manipulating processes regulated by the N-terminal modification, as there are no small molecules targeting them. The molecules they discovered demonstrate that N-terminal acetylation is a druggable target, establish paradigms for selectively inhibiting N-terminal acetylation–dependent protein interactions, and provide routes for inhibiting a specific E2–E3 ubiquitin-like protein-ligase complex to treat cancers and other disease.
N-terminal acetylation, DCN1, E2-E3 ligase
Granted Patents or Published Applications
Protected by a published pending patent application WO 2017/049295
Related Scientific References
Daniel C Scott, Jared T Hammill, Jaeki Min, David Y Rhee, Michele Connelly, Vladislav O Sviderskiy, Deepak Bhasin, Yizhe Chen, Su-Sien Ong, Sergio C Chai, Asli N Goktug, Guochang Huang, Julie K Monda, Jonathan Low, Ho Shin Kim, Joao A Paulo, Joe R Cannon, Anang A Shelat, Taosheng Chen, Ian R Kelsall, Arno F Alpi, Vishwajeeth Pagala, Xusheng Wang, Junmin Peng, Bhuvanesh Singh et al. Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase, Nature Chemical Biology, 2017, in press. doi:10.1038/nchembio.2386.
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