Structure-Activity Relationships and Biological Insights into PSMA-617 and Its Derivatives with Modified Lipophilic Linker Regions
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F25%3A00617929" target="_blank" >RIV/86652036:_____/25:00617929 - isvavai.cz</a>
Result on the web
<a href="https://pubs.acs.org/doi/10.1021/acsomega.4c10142" target="_blank" >https://pubs.acs.org/doi/10.1021/acsomega.4c10142</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acsomega.4c10142" target="_blank" >10.1021/acsomega.4c10142</a>
Alternative languages
Result language
angličtina
Original language name
Structure-Activity Relationships and Biological Insights into PSMA-617 and Its Derivatives with Modified Lipophilic Linker Regions
Original language description
PSMA-617 is recognized as a benchmark ligand for prostate-specific membrane antigen (PSMA) owing to its broad utilization in prostate cancer (PCa) targeted radionuclide therapy. In this study, the structure-activity relationships (SAR) of PSMA-617 and two novel analogs featuring modified linkers were investigated. In compounds P17 and P18, the 2-naphthyl-l-Ala moiety was replaced with a less lipophilic 3-styryl-l-Ala moiety while the cyclohexyl ring in P18 was replaced with a phenyl group. The first ever crystal structure of the PSMA/PSMA-617 complex reported here revealed a folded conformation of the PSMA-617 linker while for the PSMA/P17 and PSMA/P18 complexes, the extended orientations of the linkers revealed linker flexibility within the PSMA cavity, a change in binding that can be exploited for the structure-guided design of PSMA-targeting agents. Despite structural differences from PSMA-617, the analogs maintained high PSMA inhibition potency, cellular binding, and internalization. In vivo biodistribution studies revealed comparable tumor uptake across all three compounds with P18 displaying higher spleen accumulation, likely due to phenyl ring lipophilicity. These SAR findings provide a strategic framework for the rational design of PSMA ligands, paving the way for the development of next-generation theranostic agents for PCa.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30204 - Oncology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
ACS Omega
ISSN
2470-1343
e-ISSN
2470-1343
Volume of the periodical
10
Issue of the periodical within the volume
7
Country of publishing house
US - UNITED STATES
Number of pages
14
Pages from-to
7077-7090
UT code for WoS article
001419519100001
EID of the result in the Scopus database
2-s2.0-85217573847