(2017) Scott, Daniel C.; Hammill, Jared T.; Min, Jaeki; Rhee, David; Connelly, Michele; Sviderskiy, Vladislav O.; Bhasin, Deepak; Chen, Yizhe; Ong, Su-Sien; Chai, Sergio C.; Goktug, Asli N.; Huang, Guochang; Monda, Julie K.; Low, Jonathan; Kim, Ho Shin; Paulo, Joao; Cannon, Joe R.; Shelat, Anang A.; Chen, Taosheng; Kelsall, Ian R.; Alpi, Arno F.; Pagala, Vishwajeeth; Wang, Xusheng; Peng, Junmin; Singh, Bhuvanesh; Harper, J. Wade; Schulman, Brenda A.; Guy, R. Kip
N-terminal acetylation is an abundant modification influencing protein functions. Since ≈80% of mammalian cytosolic proteins are N-terminally acetylated, this potentially represents an untapped target for chemical control of their functions. Structural studies have revealed that, like lysine acetylation, N-terminal acetylation converts a positively charged amine into a hydrophobic handle that mediates protein interactions, suggesting it may be a druggable target. We report the development of chemical probes targeting the N-terminal acetylation-dependent interaction between an E2 conjugating enzyme (UBE2M, aka UBC12) and DCN1 (aka DCUN1D1), a subunit of a multiprotein E3 ligase for the ubiquitin-like protein NEDD8. The inhibitors are highly selective with respect to other protein acetyl amide binding sites, inhibit NEDD8 ligation in vitro and in cells, and suppress the anchorage-independent growth of a cell line harboring DCN1 amplification. Overall, the data demonstrate that N-terminal acetyl-dependent protein interactions are druggable targets, and provide insights into targeting multiprotein E2–E3 ligases.
