-
Je něco špatně v tomto záznamu ?
Structure-activity relationship and biochemical evaluation of novel fibroblast activation protein and prolyl endopeptidase inhibitors with α-ketoamide warheads
A. Šimková, T. Ormsby, N. Sidej, LP. Slavětínská, J. Brynda, J. Beranová, P. Šácha, P. Majer, J. Konvalinka
Jazyk angličtina Země Francie
Typ dokumentu časopisecké články
- MeSH
- fibroblasty metabolismus MeSH
- lidé MeSH
- molekulární struktura MeSH
- myši MeSH
- prolyloligopeptidasy metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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.
Citace poskytuje Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc22011927
- 003
- CZ-PrNML
- 005
- 20220506125856.0
- 007
- ta
- 008
- 220425s2021 fr f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1016/j.ejmech.2021.113717 $2 doi
- 035 __
- $a (PubMed)34371463
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a fr
- 100 1_
- $a Šimková, Adéla $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 542/2, 166 10, Praha 6, Czech Republic; Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, 12843, Praha 2, Czech Republic
- 245 10
- $a Structure-activity relationship and biochemical evaluation of novel fibroblast activation protein and prolyl endopeptidase inhibitors with α-ketoamide warheads / $c A. Šimková, T. Ormsby, N. Sidej, LP. Slavětínská, J. Brynda, J. Beranová, P. Šácha, P. Majer, J. Konvalinka
- 520 9_
- $a 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.
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a fibroblasty $x metabolismus $7 D005347
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a myši $7 D051379
- 650 _2
- $a molekulární struktura $7 D015394
- 650 _2
- $a prolyloligopeptidasy $x metabolismus $7 D000085822
- 650 _2
- $a vztahy mezi strukturou a aktivitou $7 D013329
- 655 _2
- $a časopisecké články $7 D016428
- 700 1_
- $a Ormsby, Tereza $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 542/2, 166 10, Praha 6, Czech Republic
- 700 1_
- $a Sidej, Natan $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 542/2, 166 10, Praha 6, Czech Republic
- 700 1_
- $a Slavětínská, Lenka Poštová $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 542/2, 166 10, Praha 6, Czech Republic
- 700 1_
- $a Brynda, Jiří $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 542/2, 166 10, Praha 6, Czech Republic
- 700 1_
- $a Beranová, Jana $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 542/2, 166 10, Praha 6, Czech Republic; First Faculty of Medicine, Charles University, Katerinska 32, 121 08, Prague 2, Czech Republic
- 700 1_
- $a Šácha, Pavel $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 542/2, 166 10, Praha 6, Czech Republic
- 700 1_
- $a Majer, Pavel $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 542/2, 166 10, Praha 6, Czech Republic
- 700 1_
- $a Konvalinka, Jan $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 542/2, 166 10, Praha 6, Czech Republic; Department of Biochemistry, Faculty of Science, Charles University, Hlavova 8, 12843, Praha 2, Czech Republic. Electronic address: konval@uochb.cas.cz
- 773 0_
- $w MED00001628 $t European journal of medicinal chemistry $x 1768-3254 $g Roč. 224, č. - (2021), s. 113717
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/34371463 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y p $z 0
- 990 __
- $a 20220425 $b ABA008
- 991 __
- $a 20220506125848 $b ABA008
- 999 __
- $a ok $b bmc $g 1789499 $s 1163128
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2021 $b 224 $c - $d 113717 $e 20210731 $i 1768-3254 $m European journal of medicinal chemistry $n Eur J Med Chem $x MED00001628
- LZP __
- $a Pubmed-20220425
