Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution

Andrew Potter, Victoria Oldfield, Claire Nunns, Christophe Fromont, Stuart Ray, Christopher J. Northfield, Christopher J. Bryant, Simon F. Scrace, David Robinson, Natalia Matossova, Lisa Baker, Pawel Dokurno, Allan E. Surgenor, Ben Davis, Christine M. Richardson, James B. Murray, Jonathan D. Moore, Andrew Potter, Victoria Oldfield, Claire Nunns, Christophe Fromont, Stuart Ray, Christopher J. Northfield, Christopher J. Bryant, Simon F. Scrace, David Robinson, Natalia Matossova, Lisa Baker, Pawel Dokurno, Allan E. Surgenor, Ben Davis, Christine M. Richardson, James B. Murray, Jonathan D. Moore, Andrew Potter, Victoria Oldfield, Claire Nunns, Christophe Fromont, Stuart Ray, Christopher J. Northfield, Christopher J. Bryant, Simon F. Scrace, David Robinson, Natalia Matossova, Lisa Baker, Pawel Dokurno, Allan E. Surgenor, Ben Davis, Christine M. Richardson, James B. Murray, Jonathan D. Moore

文献索引：Bioorg. Med. Chem. Lett. 20 , 6483, (2010)

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摘要

Structure-guided techniques were used to evolve a 5-pyridinyl pyrazole-3-carboxylate fragment into a series of 5-aryl-carbamoyl-3-phenyl-imidazole-4-carboxylates, examples of which inhibited the Pin1 PPIase with sub-μM IC 50 and blocked proliferation of prostate cancer cells.