Počet záznamů: 1
Structure-activity relationship and biochemical evaluation of novel fibroblast activation protein and prolyl endopeptidase inhibitors with α-ketoamide warheads
- 1.
SYSNO ASEP 0544791 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Structure-activity relationship and biochemical evaluation of novel fibroblast activation protein and prolyl endopeptidase inhibitors with α-ketoamide warheads Tvůrce(i) 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, ORCIDČíslo článku 113717 Zdroj.dok. European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
Roč. 224, Nov 15 (2021)Poč.str. 9 s. Jazyk dok. eng - angličtina Země vyd. FR - Francie Klíč. slova fibroblast activation protein ; seprase ; FAP inhibitor ; serine protease inhibition ; prolyl endopeptidase ; α-Ketoamide inhibitor Obor OECD Medicinal chemistry CEP GA19-10280S GA ČR - Grantová agentura ČR NV15-31379A GA MZd - Ministerstvo zdravotnictví EF16_019/0000729 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy LM2015064 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Způsob publikování Open access Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000703110000046 EID SCOPUS 85111985613 DOI 10.1016/j.ejmech.2021.113717 Anotace 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. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Rok sběru 2022 Elektronická adresa https://doi.org/10.1016/j.ejmech.2021.113717
Počet záznamů: 1