Structure guided development of novel thymidine mimetics targeting Pseudomonas aeruginosa thymidylate kinase: from hit to lead generation

…, H Soutter, J Chang, JR Miller, K Dillman…

Index: Choi, Jun Yong; Plummer, Mark S.; Starr, Jeremy; Desbonnet, Charlene R.; Soutter, Holly; Chang, Jeanne; Miller, J. Richard; Dillman, Keith; Miller, Alita A.; Roush, William R. Journal of Medicinal Chemistry, 2012 , vol. 55, # 2 p. 852 - 870

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Citation Number: 21

Abstract

Thymidylate kinase (TMK) is a potential chemotherapeutic target because it is directly involved in the synthesis of an essential component, thymidine triphosphate, in DNA replication. All reported TMK inhibitors are thymidine analogues, which might retard their development as potent therapeutics due to cell permeability and off-target activity against human TMK. A small molecule hit (1, IC50= 58 μM), which has reasonable inhibition ...