Synthesis and biological evaluation of pyrimidine derivatives as novel human Pin1 inhibitors

Bioorg Med Chem. 2018 May 1;26(8):2186-2197. doi: 10.1016/j.bmc.2018.03.024. Epub 2018 Mar 15.

Abstract

Pin1 (Protein interacting with NIMA1) is a cis-trans isomerase and promotes the amide bond rotation of phosphoSer/Thr-Pro motifs in its substrates. Inhibition of Pin1 might be a novel strategy for developing anticancer agents. Herein, a series of pyrimidine derivatives were synthesized and their Pin1 inhibitory activities were evaluated. Among them, four compounds (2a, 2f, 2h and 2l) displayed potent inhibitory activities against Pin1 with IC50 values lower than 3 µM. This series of pyrimidine-based inhibitors presented time-dependent inhibition against Pin1. The structure-activity relationships on the 2-, 4- and 5-positions of the pyrimidine ring were analyzed in details, which would facilitate further exploration of new Pin1 inhibitors.

Keywords: Anti-cancer agents; PPIase; Pin1; Pin1 inhibitor; Pyrimidine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Humans
  • NIMA-Interacting Peptidylprolyl Isomerase / antagonists & inhibitors*
  • NIMA-Interacting Peptidylprolyl Isomerase / genetics
  • NIMA-Interacting Peptidylprolyl Isomerase / metabolism
  • Protein Binding
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Pyrimidines
  • Recombinant Proteins
  • PIN1 protein, human