Abstract 2165: Structure activity relationship of a novel chemical class of Dyrk inhibitors.
Authors: Casagrande Anne-Sophie , Bachelot Florence , Coutadeur Séverine , Leblond Bertrand , Besson Thierry , Pando Matthew P. , Désiré Laurent 
Published: August 2014

Abstract
Dual-specificity tyrosine-phosphorylated and regulated kinases (DYRK) is a family of conserved protein kinases which mediate survival and differentiation in normal tissues like skeletal muscle for Mirk/Dyrk1B or neuronal cells for Dyrk1A. Among the five Dyrk proteins, Mirk/Dyrk1B has very low level of expression in most normal cell types but has been found to be upregulated in solid tumors and to mediate cell survival in colon cancer, pancreatic ductal adenocarcinoma, rhabdomyosarcomas, lung and ovarian cancer. Mirk/Dyrk1B expression and abundance varies during the cell cycle with the highest levels found in quiescent G0 phase where it mediates G0 tumor cells prolonged survival (through increasing expression of a cohort of antioxidant genes). Dyrk1A also promotes quiescence and senescence through DREAM complex assembly by phosphorylating the DREAM subunit LIN52. The ability of cells to exit from the cell cycle and enter into the G0 or quiescence state is important for cell differentiation, tissue development, and prevention of tumorigenesis. Tumors may contain a fraction of quiescent cells responsible for resistance to chemotherapy and radiation, serving as a reservoir for tumor repopulation post-therapy. Thus, pharmacological Dyrk inhibition would reduce the ability of cells to enter into quiescence and sensitize cancer cells to conventional chemotherapeutic agents. Exonhit has developed a novel class of DYRK inhibitors. Lead optimization led to the synthesis of new chemical entities with subnanomolar kinase inhibitory activities associated with a high degree of selectivity over 400 kinases. Most active compounds were evaluated in various cellular models, demonstrating good correlation between cellular activity and amplification/expression of Mirk/Dyrk1B. Similarly, in accordance with the expression levels of Mirk/Dyrk1B during the cell cycle, cellular potency of pharmacological inhibitors was improved 3 to 11 fold in SW620 quiescent cultures when compared to cycling cultures. We analyzed the effects of Dyrk inhibitors alone and in combination with gemcitabine in the Panc1 pancreatic cancer cell line multicellular tumor spheroid model described to be largely quiescent and enriched in Mirk/Dyrk1B kinase and confirmed that Dyrk inhibitors sensitize cells to gemcitabine with a synergistic effect of the combination. Among the 120 NCEs from this series, we identified lead compounds having potent in vitro efficacy as Dyrk inhibitors. These compounds are being further characterized in various cellular studies and show promising in vivo activities in patient-derived ovarian cancer ascites spheroids and Panc1 xenografts model without detectable toxicity in mice, establishing the usefulness of these inhibitors for targeting cancer cells with high Dyrk kinase activity.
Citation Format: Anne-Sophie Casagrande, Florence Bachelot, Séverine Coutadeur, Bertrand Leblond, Thierry Besson, Matthew P. Pando, Laurent Désiré. Structure activity relationship of a novel chemical class of Dyrk inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2165. doi:10.1158/1538-7445.AM2013-2165