3KAH

Structure-guided design of alpha-amino acid-derived Pin1 inhibitors

Summary for 3KAH

• Entry DOI: 10.2210/pdb3kah/pdb
• Related: 3KAB 3KAC 3KAD 3KAF 3KAG 3KAI 3KCE
• Descriptor: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, DODECAETHYLENE GLYCOL, 3-(1H-benzimidazol-2-yl)-N-[(1-methyl-3-phenyl-1H-pyrazol-5-yl)carbonyl]-D-alanine, ... (4 entities in total)
• Functional Keywords: sbdd, ppiase, isomerase, rotamase, small molecule, proline directed kinase, cell cycle, oncogenic transformation, nucleus, phosphoprotein
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q13526
• Total number of polymer chains: 1
• Total formula weight: 19460.58

Authors

Baker, L.M.,Dokurno, P.,Robinson, D.A.,Surgenor, A.E.,Murray, J.B.,Potter, A.J.,Moore, J.D. (deposition date: 2009-10-19, release date: 2009-12-22, Last modification date: 2023-11-01)

Primary citation

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.
Structure-guided design of alpha-amino acid-derived Pin1 inhibitors
Bioorg.Med.Chem.Lett., 20:586-590, 2010

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.

PubMed: 19969456
DOI: 10.1016/j.bmcl.2009.11.090

Experimental method

X-RAY DIFFRACTION (2.3 Å)