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• W2953669336 abstract "Abstract Introduction: Gankyrin is an oncoprotein involved in regulating numerous pathways important to cell growth, signaling, proliferation and death. The overexpression of gankyrin and subsequent increased protein-protein interactions have been identified as key to increased proliferation in a variety of cancers. Consequently, small molecules that bind to and disrupt these protein-protein interactions are promising therapeutic strategies for the treatment of certain cancers. The first small molecule binder of gankyrin, cjoc42, was recently developed and exhibited efficacy in inhibiting the gankyrin-26S proteasome interaction. The aim of this work is to determine the effects of cjoc42 and its derivatives on cell migration and proliferation in gankyrin-overexpressing cancers. Methods: Wound healing and CyQuant proliferation assays were used to determine the ability of cjoc42 to inhibit migration and proliferation in the gankyrin-overexpressing cell lines A549, MDA-MB231 and Huh6 cells. A protein thermal shift assay was used to screen new cjoc42 derivatives for their ability to bind gankyrin. Western blot experiments will determine if binding of cjoc42 and its derivatives to gankyrin is the mechanism of action in cells. Results: Cjoc42 demonstrated an ability to inhibit the migratory and proliferative activity of A549 and MDA-MB231 cells. While only a modest inhibition of migration was observed, cjoc42 exhibited a significant antiproliferative effect against these cell lines. Utilization of a protein thermal shift assay yielded cjoc42 derivatives with more potent gankyrin-binding ability. These compounds will be evaluated in-cellulo for their ability to inhibit cell migration and proliferation. Western blot experiments will confirm that gankyrin-binding of cjoc42 attributes to the anti-migration and anti-proliferative effects observed. Conclusions: These studies show that cjoc42 directly inhibits cell migration and proliferation by inhibiting the interaction between gankyrin and the 26S proteasome. Consequently, this work provides background for the development of small molecule inhibitors as a gankyrin-mediated therapy for the treatment of lung, breast and liver cancers. Citation Format: Pamela Farrales, Aaron Muth. Small molecule targeting of gankyrin reduces cell migration and proliferation in certain cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 23." @default.
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• W2953669336 date "2019-07-01" @default.
• W2953669336 modified "2023-09-27" @default.
• W2953669336 title "Abstract 23: Small molecule targeting of gankyrin reduces cell migration and proliferation in certain cancers" @default.
• W2953669336 doi "https://doi.org/10.1158/1538-7445.am2019-23" @default.
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