Discovery of deoxyvasicinone derivatives as inhibitors of NEDD8-activating enzyme
School of Chinese Medicine
NEDD8-activating enzyme (NAE) controls the specific degradation of proteins regulated by cullin-RING ubiquitin E3 ligases, and has been considered as an attractive molecular target for the development of drugs against cancer. A pharmacophore model constructed from a training set of deoxyvasicinone derivatives was used to screen 376 compounds from an analogue database. From the initial screening, the valine-linked deoxyvasicinone derivative 9 and the N-isopropyl-linked deoxyvasicinone derivative 10 emerged as the top scoring candidates. Compounds 9 and 10 showed micromolar potencies in both cell-free and cell-based systems, with selectivity for NAE over the related enzymes SAE and UAE. Molecular modelling analysis suggested that 9 and 10 may inhibit NAE by blocking the ATP-binding domain. Thus, these deoxyvasicinone derivatives could be considered as promising lead molecules for the development of more potent inhibitors of NAE.
Drug discovery, Ubiquitin-like, NEDD8, Deoxyvasicinone, Pharmacophore
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Zhong, H., Leung, K., Lin, S., Chan, D., Han, Q., Chan, S., Ma, D., & Leung, C. (2015). Discovery of deoxyvasicinone derivatives as inhibitors of NEDD8-activating enzyme. Methods, 71 (). https://doi.org/10.1016/j.ymeth.2014.08.014