Download MendeleyStructure-guided design of alpha-amino acid-derived Pin1 inhibitors
Potter, A.J., Ray, S., Gueritz, L., Nunns, C.L., Bryant, C.J., Scrace, S.F., Matassova, N., Baker, L.M., Dokurno, P., Robinson, D.A., Surgenor, A.E., Davis, B., Murray, J.B., Richardson, C.M., Moore, J.D.(2010) Bioorg Med Chem Lett 20: 586-590
- PubMed: 19969456
- DOI: https://doi.org/10.1016/j.bmcl.2009.11.090
- Primary Citation of Related Structures:
3KAB, 3KAC, 3KAD, 3KAF, 3KAG, 3KAH, 3KAI, 3KCE - PubMed Abstract:
The peptidyl prolyl cis/trans isomerase Pin1 is a promising molecular target for anti-cancer therapeutics. Here we report the structure-guided evolution of an indole 2-carboxylic acid fragment hit into a series of alpha-benzimidazolyl-substituted amino acids. Examples inhibited Pin1 activity with IC(50) <100nM, but were inactive on cells. Replacement of the benzimidazole ring with a naphthyl group resulted in a 10-50-fold loss in ligand potency, but these examples downregulated biomarkers of Pin1 activity and blocked proliferation of PC3 cells.
Organizational Affiliation:
Vernalis (R&D) Ltd, Granta Park, Great Abington, Cambridge CB21 6GB, United Kingdom.
