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

A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action

“…The compound pool was first filtered applying the Lipinski's rule of five criteria for enhanced drug-likeness. Then, a virtual structure-based screening was performed using the crystal structure of human PIN1 (PDB entry 2XPB)16. The compounds showing the higher docking scores were then subjected to another virtual screening specifically designed to identify compounds able to covalently target the active site residue C113.…”

“…Compounds were subsequently filtered in Canvas using the following chemical property ranges that correspond to the Lipinski's rule of five for enhanced drug-likeness: MW 300–550, hydrogen-bond donors 0-5, hydrogen-bond acceptors 1–10, Rotatable bonds<10, AlogP<5.5, Total charge -1à1, PSA <140. The PIN1 structure (PDBID: 2XPB)16 was used for structure-based screening following protein preparation in Maestro (Maestro v9.2. (2011) Schrödinger, Inc., Portland).…”

“…21). Three-dimensional (3D) structures of PIN1 (PDBID: 2XPB)16 were retrieved from the Protein Data Bank (www.rcsb.org). The protein structures were organized using the Protein Preparation Wizard, whereas the 3D structure of the ligand was optimized using LigPrep module and the partial charges were ascribed using Optimized Potentials for Liquid Simulations (OPLS3) force-field53.…”

Prolyl Isomerase Pin1 Negatively Regulates AMP-activated Protein Kinase (AMPK) by Associating with the CBS Domain in the γ Subunit

“…Thus, we employed not only Juglone but also two other Pin1 inhibitor types possibly more highly specific for Pin1, both of which were custom-made by SundiaMediTech Company Ltd. (Shanghai, China). The one termed Pin1 inhibitor 1 is (R)-2-(5-(4-methoxyphenyl)-2-methylfuran-3-caroxamido)-3-(naphthalen-6-yl) propanoic acid (32), and the other, termed Pin1 inhibitor 2, is 4-(N-benzyl- (33). These inhibitors were added to cells 30 min prior to 2-deoxyglucose (2-DG) treatment.…”

Structure and function of the human parvulins Pin1 and Par14/17

“…DTM is a putative competitor of Pin1 substrates that is capable of inhibiting the proliferation of HCT116 colon carcinoma cells. In addition, synthetic Pin1 directed imidazole and isothiazole derivatives (Mori et al, 2011) and substituted phenyl-imidazoles (Potter et al, 2010) have cytotoxic effects and lead to growth arrest in cancer cells. The polyphenol epigallocatechin-3-gallate (EGCG) inactivates Pin1 by blocking the binding sites for pSer-Pro substrates within the PPIase and the WW-domain (Urusova et al, 2011;Xi et al, 2016), thereby, preventing tumor growth.…”