Abstract 5237: Targeting DCN1-mediated neddylation in lung SCC with novel small-molecule inhibitors

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Abstract Due to the anti-neoplastic properties and clinical successes of the proteasome inhibitors Bortezomib and Carfilzomib, the ubiquitin-proteasome system (UPS) has become a new target of interest in oncology research. The clinical toxicity induced by these inhibitors, likely caused by complete inhibition of the UPS, has resulted in a need for the development of more selective UPS regulators. A more in depth understanding of the intrinsic molecular mechanisms that are associated with the UPS has unmasked the potential for improved therapies via more specific targets such as the process of neddylation, which is thought to control 15 - 20% of the UPS (5). During neddylation, an enzyme known as DCN1 for “defective in cullin neddylation 1” functions as a co-E3 to help steer a ubiquitin-like protein (UBL), NEDD8, from an E2 enzyme, UBC12, to a cullin (CUL) neddylation site (6 - 7, 9 - 11). Because DCN1 has been found to be amplified in certain squamous cell carcinomas (9) (SCCs; e.g. lung, esophagus, and head and neck), this in vitro, pre-clinical study demonstrates the potential of the DCN1-UBC12 interaction as a therapeutic site in lung SCCs through the use of novel small-molecule inhibitors from the St. Jude (SJ) library. After optimizing dosing regimens, it has been determined that re-administering the SJ compounds (i.e. SJ690, SJ447, SJ446, and SJ323) every 24-hours to address the issue of protein turn-over, produces more efficacious treatment. The most biochemically-potent antagonists in the compound series were also shown in these primary cell lines to potentiate other therapeutic agents such as Cisplatin; however, these compounds alone do not induce DNA damage, nor do they elicit caspase 3/7 activity. Nonetheless, combination treatment of the SJ compounds with Staurosporine in SCC cell lines, potentiated caspase 3/7 activity at varying degrees. Collectively, this data enhances our understanding of the mechanism by which the inhibition of DCN1 affects cancer cells, informing pre-clinical development of the SJ DCN1 antagonists. Citation Format: Richard Barrios, Jared Hammill, Jaeki Min, Kip Guy. Targeting DCN1-mediated neddylation in lung SCC with novel small-molecule inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5237. doi:10.1158/1538-7445.AM2017-5237