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

• Published in: Bioorganic & medicinal chemistry letters 2010-11, Vol.20 (22), p.6483-6488
• Main Authors: Potter, Andrew, Oldfield, Victoria, Nunns, Claire, Fromont, Christophe, Ray, Stuart, Northfield, Christopher J., Bryant, Christopher J., Scrace, Simon F., Robinson, David, Matossova, Natalia, Baker, Lisa, Dokurno, Pawel, Surgenor, Allan E., Davis, Ben, Richardson, Christine M., Murray, James B., Moore, Jonathan D.
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Caco-2 Cells; Cancer; Drug Discovery; Fragments; General aspects; Humans; Imidazoles - chemistry; Imidazoles - pharmacology; Medical sciences; Models, Molecular; Molecular Structure; NIMA-Interacting Peptidylprolyl Isomerase; Peptidyl prolyl isomerase; Peptidylprolyl Isomerase - antagonists & inhibitors; Pharmacology. Drug treatments; Pin1
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.09.063

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 IC50 and blocked proliferation of prostate cancer cells. Pin1 is an emerging oncology target strongly implicated in Ras and ErbB2-mediated tumourigenesis. Pin1 isomerizes bonds linking phospho-serine/threonine moieties to proline enabling it to play a key role in proline-directed kinase signalling. Here we report a novel series of Pin1 inhibitors based on a phenyl imidazole acid core that contains sub-μM inhibitors. Compounds have been identified that block prostate cancer cell growth under conditions where Pin1 is essential.