title: Structure-based design of novel human Pin1 inhibitors (III): optimizing affinity beyond the phosphate recognition pocket.
abstract: The design of potent Pin1 inhibitors has been challenging because its active site specifically recognizes a phospho-protein epitope. The de novo design of phosphate-based Pin1 inhibitors focusing on the phosphate recognition pocket and the successful replacement of the phosphate group with a carboxylate have been previously reported. The potency of the carboxylate series is now further improved through structure-based optimization of ligand-protein interactions in the proline binding site which exploits the H-bond interactions necessary for Pin1 catalytic function. Further optimization using a focused library approach led to the discovery of low nanomolar non-phosphate small molecular Pin1 inhibitors. Structural modifications designed to improve cell permeability resulted in Pin1 inhibitors with low micromolar anti-proliferative activities against cancer cells.
authors.affiliation: Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA. Electronic address: alexguo01@gmail.com.
authors.forename: Chuangxing
authors.initials: C
authors.lastname: Guo
authors.affiliation: Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
authors.forename: Xinjun
authors.initials: X
authors.lastname: Hou
authors.affiliation: Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Dong
authors.affiliation: Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Marakovits
authors.affiliation: Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Greasley
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Dagostino
authors.affiliation: Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
authors.forename: RoseAnn
authors.initials: R
authors.lastname: Ferre
authors.affiliation: Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
authors.forename: M Catherine
authors.initials: MC
authors.lastname: Johnson
authors.affiliation: Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Humphries
authors.affiliation: Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.affiliation: Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
authors.forename: Genevieve D
authors.initials: GD
authors.lastname: Paderes
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Piraino
authors.affiliation: Pharmacokinetics and Drug Metabolism, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Kraynov
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA. Electronic address: brion.murray@pfizer.com.
authors.forename: Brion W
authors.initials: BW
authors.lastname: Murray
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010710:Phosphates / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010710:Phosphates; C031000:benzimidazole; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase
keywords: Anti-cancer; Anti-tumor; Cell permeability; Medicinal chemistry; Mitosis; PPIase; Peptidyl-prolyl isomerase; Phospho-protein epitope; Pin1; SBDD; Structural based drug design