2. Academic Validation
  3. Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery

Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery

  • Bioorg Med Chem. 2014 Aug 1;22(15):4099-108. doi: 10.1016/j.bmc.2014.05.061.
Jan Tykvart 1,  Jiří Schimer 1,  Jitka Bařinková 2,  Petr Pachl 3,  Lenka Poštová-Slavětínská 2,  Pavel Majer 2,  Jan Konvalinka 1,  Pavel Šácha 4
Affiliations

Affiliations

  • 1 Gilead Sciences and IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, Prague 6, 166 10 Czech Republic; Department of Biochemistry, Faculty of Natural Science, Charles University, Albertov 6, Prague 2, Czech Republic.
  • 2 Gilead Sciences and IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, Prague 6, 166 10 Czech Republic.
  • 3 Gilead Sciences and IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, Prague 6, 166 10 Czech Republic; Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Vídeňská 1083, Prague 4, Czech Republic.
  • 4 Gilead Sciences and IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, Prague 6, 166 10 Czech Republic; Department of Biochemistry, Faculty of Natural Science, Charles University, Albertov 6, Prague 2, Czech Republic. Electronic address: pavelsacha@gmail.com.
PMID: 24954515 DOI: 10.1016/j.bmc.2014.05.061
Abstract

Glutamate Carboxypeptidase II (GCPII), also known as prostate specific membrane antigen (PSMA), is an established prostate Cancer marker and is considered a promising target for specific anticancer Drug Delivery. Low-molecular-weight inhibitors of GCPII are advantageous specific ligands for this purpose. However, they must be modified with a linker to enable connection of the ligand with an imaging molecule, Anticancer drug, and/or nanocarrier. Here, we describe a structure-activity relationship (SAR) study of GCPII inhibitors with linkers suitable for imaging and Drug Delivery. Structure-assisted inhibitor design and targeting of a specific GCPII exosite resulted in a 7-fold improvement in Ki value compared to the parent structure. X-ray structural analysis of the inhibitor series led to the identification of several inhibitor binding modes. We also optimized the length of the inhibitor linker for effective attachment to a biotin-binding molecule and showed that the optimized inhibitor could be used to target nanoparticles to cells expressing GCPII.

Keywords

GCPII; PSMA; Specific drug targeting; Structure-aided drug design.

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