Improving the Selectivity of PACE4 Inhibitors through Modifications of the P1 Residue.
J Med Chem
; 61(24): 11250-11260, 2018 12 27.
Article
en En
| MEDLINE
| ID: mdl-30501188
ABSTRACT
Paired basic amino acid cleaving enzyme 4 (PACE4), a serine endoprotease of the proprotein convertases family, has been recognized as a promising target for prostate cancer. We previously reported a selective and potent peptide-based inhibitor for PACE4, named the multi-Leu peptide (Ac-LLLLRVKR-NH2 sequence), which was then modified into a more potent and stable compound named C23 with the following structure Ac-dLeu-LLLRVK-Amba (Amba 4-amidinobenzylamide). Despite improvements in both in vitro and in vivo profiles of C23, its selectivity for PACE4 over furin was significantly reduced. We examined other Arg-mimetics instead of Amba to regain the lost selectivity. Our results indicated that the replacement of Amba with 5-(aminomethyl)picolinimidamide increased affinity for PACE4 and restored selectivity. Our results also provide a better insight on how structural differences between S1 pockets of PACE4 and furin could be employed in the rational design of selective inhibitors.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Inhibidores de Serina Proteinasa
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Proproteína Convertasas
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Antineoplásicos
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2018
Tipo del documento:
Article