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Title: | DEVELOPMENT OF SMALL MOLECULE INHIBITORS FOR THE INHIBITION OF PRO-SURVIVAL MCL-1 PROTEIN | Authors: | TANG SHI QING | Keywords: | Mcl-1, heterocycle, fragment-based design, metabolic stability, toxicity, Michael-acceptor reactivity | Issue Date: | 17-Sep-2015 | Citation: | TANG SHI QING (2015-09-17). DEVELOPMENT OF SMALL MOLECULE INHIBITORS FOR THE INHIBITION OF PRO-SURVIVAL MCL-1 PROTEIN. ScholarBank@NUS Repository. | Abstract: | Overexpression of Mcl-1 plays a major role in the survival and resistance of cancer cells towards chemotherapy. Thus there is an urgent need to develop small molecule inhibitors (SMIs) that are potent inhibitors of Mcl-1 protein. However, to date, there is a paucity of information on the physical and structural features that is needed in SMIs that would lead to effective and selective binding to Mcl-1. The aim of this project is to identify the key physical structural determinants of SMIs for Mcl-1 binding by evaluating the activities of series of five-membered multi-heterocyclic (FMMH) compounds, namely the rhodanines, 2-thiohydantoins, 2,4-thiazolidinediones and hydantoins. Subsequently, the physical and structural features determined are used for fragment-based screening to identify new scaffolds for Mcl-1 protein inhibition. The metabolic stabilities, toxicities and Michael-acceptor reactivities are also evaluated to bridge the gap in the literature to properly evaluate the suitability of these scaffolds in drug discovery.. | URI: | http://scholarbank.nus.edu.sg/handle/10635/122484 |
Appears in Collections: | Ph.D Theses (Open) |
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