Synthesis and evaluation of ubiquitin ligase inhibitors as anticancer leads Jake M Rigby 1 , Ashley Dudey 2 , Andrew Chantry 2 , Andrew M. Hemmings 2 , G Richard Stephenson 1 , Tom E. Storr* 1 1 School of Chemistry,University of East Anglia, UK, 2 School of Biological Sciences,University of East Anglia, UK The ubiquitin proteasome system (UPS) is essential for the regulation of cellular protein quality and quantity within cells. 1 Within the UPS, E3 ligases are selective for certain proteins, tagging them with ubiquitin for eventual protein degradation. WWP2 is a HECT E3 ligase overexpressed in several forms of cancers, such as oral and prostate cancers, suggesting WWP2 and its isoforms could be promising disease targets. 2,3,4 Within the research group, several molecules have been investigated for inhibitory activity against WWP2 by utilising STD and DEEP- STD NMR. 5 Currently we are exploring the synthesis and functionalisation of a number of hits with heterocyclic cores, including imidazo[4,5- b ]pyrazine,indole, alloxazine, isoquinolineas well as biaryland benzidine cores. Molecular docking is being utilised to aid in the design of analogues for structure-activity studies. References 1. L. Deng, T. Meng, L. Chen, W. Wei and P. Wang, Signal Transduct. Target. Ther , 2020, 5 , 1-28. 2. A. Chantry, Cell Cycle , 2011, 10 , 2437–2439. 3. C. Fukumoto, D. Nakashima, A. Kasamatsu, M. Unozawa, T. Shida-Sakazume, M. Higo, K. Ogawara, H. Yokoe, M. Shiiba, H. Tanzawa and K. Uzawa, Oncoscience , 2014, 1 , 807–820. 4. X. Zou, G. Levy-Cohen and M. Blank, Biochim. Biophys. Acta - Rev. Cancer , 2015, 1856 , 91–106. 5. J. E. Watt, G. R. Hughes, S. Walpole, G. R. Stephenson, C. B. Page, A. M. Hemmings, J. Angulo and A. Chantry, Chem. Eur. J . 2018, 24 , 17677–17680.
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