Abstract 1337: Exploration of 2-aryl fused thiophene analogs as selective inhibitors of MEK5

Abstract

Abstract In several cancers intermediate enzymes in the MAPK cascades are up-regulated and may represent adaptive changes giving these cancers a competitive metabolic edge over normal cells. Additionally these alterations may induce resistance to previously useful chemotherapeutic agents. The enzyme MEK5, a component of the MEK5/ERK5 cascade, is up-regulated in several cancer types including triple negative breast cancer and prostrate cancers. Our group has previously described the synthesis and testing of anthranillic acid derived compounds and their ring constrained analogs. To explore chemical functional group tolerance and preference on the central arene ring by MEK5, a series of fused-thiophene ring variations, obtainable by the Gewald reaction were prepared and tested. These compounds were examined at 10 μM with MDA-MB-231 cells treated with EGF to induce MEK1/2 and MEK5 phosphorylation. Western blot analysis using IR-tagged antibodies against pERK1/2, pERK5, ERK1/2, or ERK5 was used to determine total and relative inhibition of MEK-mediated phosphorylation of respective pERK products. Incubation with PD0325901 resulted in full suppression of both pERK1/2 and pERK5. For the variations explored, several novel compounds were identified that resulted in no inhibition in the formation of pERK1/2 and 70% inhibition of pERK5. This establishes a new structural class of selective Type III inhibitors of MEK5 that are more amenable to structural variation, facilitating additional structure activity relationship studies. Citation Format: Patrick T. Flaherty, Dhruv Shah, Mohit Gupta, Thomas Wright, Jane E. Cavanaugh, Matthew E. Burow. Exploration of 2-aryl fused thiophene analogs as selective inhibitors of MEK5. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1337.