Targeting Glycogen Metabolism as a Novel Therapeutic Approach in Anaplastic Thyroid Cancer

Effective treatment options for well-differentiated papillary (PTC) and follicular (FTC) thyroid cancers afford positive patient prognoses. The absence of effective interventions for the stem-like, dedifferentiated anaplastic thyroid cancer (ATC) results in poor patient outcomes with a mortality rate higher than all other endocrine cancers combined (1). While receptor tyrosine kinase inhibitors such as sorafenib can extend ATC patient survival, drug resistance and tumor reoccurrence often develop (2). Therefore, there is a critical need for more effective targeted therapies for ATC. Although the cell signaling landscape of ATC tumors is well described, very little is known about tumorigenic adaptations in ATC cellular metabolism. Tumors exhibit an increased consumption of glucose compared to normal tissues to fuel tumor progression. Some cancers meet this high glucose requirement by storing and breaking down glycogen. In our studies here, we show for the first time that normal thyroid, PTC, FTC, and ATC cells express genes necessary for glycogen metabolism. We confirm these observations in patient samples in normal thyroid and thyroid cancer patient samples via immunofluorescence in tissue microarrays. Furthermore, we detect intracellular glycogen stores in cell lines representing normal thyroid, PTC, FTC, and ATC cells. Importantly, we demonstrate that glycogen phosphorylase inhibitors result in accumulation of intracellular glycogen and induce subsequent apoptosis in ATC cells. We further show that glycogen phosphorylase inhibitors synergize with kinase inhibitors such as sorafenib and buparlisib to decrease ATC cell viability. Our work establishes glycogen metabolism as a novel metabolic process in thyroid cells that is associated with thyroid cancer dedifferentiation and provides insight to the effectiveness of inhibiting glycogen metabolism as a therapeutic strategy in ATC. References: 1. Siegel, R.L., Miller, K.D. and Jemal, A. (2017), Cancer statistics, 2017. CA: A Cancer Journal for Clinicians, 67: 7-30. doi:10.3322/caac.21387 2. Saini S, Tulla K, Maker AV, Burman KD, Prabhakar BS. Therapeutic Advances in Anaplastic Thyroid Cancer: A Current Perspective. Mol Cancer. 2018;17(1):154. doi:10.1186/s12943-018-0903-0

Discovery and evaluation of novel benzazepinone derivatives as glycogen phosphorylase inhibitors with potent activity

Glycogen phosphorylase (GP) is a key enzyme of glycogen catabolism, so it is significant to discover a new GP inhibitor. A series of benzazepinone derivatives were discovered as GP inhibitors with potent activity. Among these derivatives, compound 5d showed significant potential against rabbit muscle GPa (IC50 = 0.25 ± 0.05 μM) and cellular efficacy. The in vivo study revealed that 5d significantly inhibited increases in fasting blood glucose level in two kinds of hyperglycemic mice models. The possible binding mode of compound 5d was explored based on molecular docking simulations. These results indicated that derivatives with benzazepinone were potential chemical entities against hyperglycemia.

Mechanochemical Synthesis and reactivity of 1,2,3-Triazole Carbohydrate Derivatives as Glycogen Phosphorylase Inhibitors

Aims: In this aim, we have developed this work to recommend an original route for the preparation of triazole derivatives. Background: Carbohydrates containing 1,2,3-triazole derivatives have various biological activities. Due to their advantageous and biological property, they are eye-catching synthetic targets in the arsenal of organic chemistry. Thus, finding green and efficient methods, as well as using ball millig procedure for the synthesis of these heterocycles is of interest to organic chemistry researchers. Objective: The objective of this study was to synthesize carbohydrate-derived triazoles under high-speed vibration milling conditions and investigate their properties. Materials and Method: A mixture of glycoside azide derivatives (1 mmol) and prop-2-yn-1-ol (1.5 mmol) in the presence of copper (I) was vigorously shaken under vibration milling conditions at 650 rpm with three balls for 15 min. The deprotection of the resulting triazole derivatives was effected by treatment with 4M hydrochloric acid in methanol under reflux. Results and Discussion: A short and convenient route to synthesize carbohydrate-derived triazoles, based in a ball-mill via 1,3-dipolar cycloaddition reactions to prop-2-yn-1-ol was developed. Cleavage of the isopropylidene protecting group provided water-soluble triazoles, evaluated as glycogen phosphorylase inhibitors. 1-[6-(4-Hydroxymethyl-[1,2,3]triazol-1-yl)- 2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-ethane-1,2-diol was the best inhibitor of rabbit muscle glycogen phosphorylase b (IC50 = 60 μM). Conclusion: In summary, we developed new, short and convenient routes to glucose-derived 1,2,3-triazole based on 1,3- dipolar cycloaddition reactions flowed by ball milling. Use of isopropylidene protective groups gave access to the analogous deprotected water-soluble motifs, analogous to known inhibitors of glycogen phosphorylase.