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Structure-activity relationship and biochemical evaluation of novel fibroblast activation protein and prolyl endopeptidase inhibitors with α-ketoamide warheads
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SYSNO ASEP 0544791 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Structure-activity relationship and biochemical evaluation of novel fibroblast activation protein and prolyl endopeptidase inhibitors with α-ketoamide warheads Author(s) Šimková, Adéla (UOCHB-X) ORCID, RID
Ormsby, Tereza (UOCHB-X) ORCID, RID
Sidej, Natan (UOCHB-X) ORCID
Poštová Slavětínská, Lenka (UOCHB-X) RID
Brynda, Jiří (UOCHB-X) RID, ORCID
Beranová, Jana (UOCHB-X) ORCID
Šácha, Pavel (UOCHB-X) RID, ORCID
Majer, Pavel (UOCHB-X)
Konvalinka, Jan (UOCHB-X) RID, ORCIDArticle number 113717 Source Title European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
Roč. 224, Nov 15 (2021)Number of pages 9 s. Language eng - English Country FR - France Keywords fibroblast activation protein ; seprase ; FAP inhibitor ; serine protease inhibition ; prolyl endopeptidase ; α-Ketoamide inhibitor OECD category Medicinal chemistry R&D Projects GA19-10280S GA ČR - Czech Science Foundation (CSF) NV15-31379A GA MZd - Ministry of Health (MZ) EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2015064 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 000703110000046 EID SCOPUS 85111985613 DOI 10.1016/j.ejmech.2021.113717 Annotation Peptidomimetic inhibitors of fibroblast activation protein (FAP) are regarded as promising tools for tumor targeting in vivo. Even though several peptidomimetic compounds with nanomolar potency have been described, broad chemical space for further modification remained unexplored. Therefore, we set to analyze the structure-activity relationship (SAR) of pseudopeptide compound series with α-ketoamide warheads in order to explore the contributions of the P1′ and P2′ moieties to the inhibitory potency. A series of novel inhibitors bearing varied P1′ and/or P2’ moieties was synthesized by combining a Passerini reaction-Amine Deprotection-Acyl Migration (PADAM) approach with peptide coupling and subsequent oxidation. The resulting compounds inhibited FAP and the related prolyl endopeptidase (PREP) with potencies in the nanomolar to sub-nanomolar range. The most potent FAP inhibitor IOCB22-AP446 (6d, IC50 = 89 pM) had about 36-fold higher inhibition potency than the most potent inhibitor published to date. The compounds were selective over FAP's closest homolog DPP-IV, were stable in human and mouse plasma and in mouse microsomes, and displayed minimal cytotoxicity in tissue cultures. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Year of Publishing 2022 Electronic address https://doi.org/10.1016/j.ejmech.2021.113717
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