Novel beta- and gamma-Amino Acid-Derived Inhibitors of Prostate-Specific Membrane Antigen

0534673 - BTÚ 2021 RIV US eng J - Journal Article
Kim, K. - Kwon, H. - Bařinka, Cyril - Motlová, Lucia - Nam, S. - Choi, D. - Ha, H. - Nam, H. - Son, S.-H. - Minn, I. - Pomper, M.G. - Yang, X. - Kutil, Zsofia - Byun, Y.
Novel beta- and gamma-Amino Acid-Derived Inhibitors of Prostate-Specific Membrane Antigen.
Journal of Medicinal Chemistry. Roč. 63, č. 6 (2020), s. 3261-3273. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA ČR(CZ) GJ19-22269Y; GA MŠMT(CZ) ED1.1.00/02.0109
Institutional support: RVO:86652036
Keywords : glutamate-carboxypeptidase-ii * urea-based inhibitors * preclinical evaluation * psma inhibitor * high-affinity
OECD category: Medicinal chemistry
Impact factor: 7.446, year: 2020
Method of publishing: Open access
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b02022

Prostate-specific membrane antigen (PSMA) is an excellent biomarker for the early diagnosis of prostate cancer progression and metastasis. The most promising PSMA-targeted agents in the clinical phase are based on the Lys-urea-Glu motif, in which Lys and Glu are alpha-(L)-amino acids. In this study, we aimed to determine the effect of beta- and gamma-amino acids in the S1 pocket on the binding affinity for PSMA. We synthesized and evaluated the beta- and gamma-amino acid analogues with (S)- or (R)-configuration with keeping alpha-(L)-Glu as the S1'-binding pharmacophore. The structure-activity relationship studies identified that compound 13c, a beta-amino acid analogue with (R)-configuration, exhibited the most potent PSMA inhibitory activity with an IC50 value of 3.97 nM. The X-ray crystal structure of PSMA in complex with 13c provided a mechanistic basis for the stereochemical preference of PSMA, which can guide the development of future PSMA inhibitors.
Permanent Link: http://hdl.handle.net/11104/0312850