A Guanidyl-Based Bivalent Peptidomimetic Inhibits K-Ras Prenylation and Association with c-Raf.

Autor: Tsubamoto M; The Institute of Scientific Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka, 567-0047, Japan., Le TK; Academic Assembly, Institute of Agriculture, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano, 399-4598, Japan., Li M; Department of Pharmaceutical Science, University of South Florida, Tampa, Florida, 33612, USA., Watanabe T; Ina Laboratory, Medical & Biological Laboratories, CO., Ltd., Ina, Nagano, 396-0002, Japan., Matsumi C; Ina Laboratory, Medical & Biological Laboratories, CO., Ltd., Ina, Nagano, 396-0002, Japan., Parvatkar P; Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto, 611-0011, Japan., Fujii H; Academic Assembly, Institute of Agriculture, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano, 399-4598, Japan., Kato N; The Institute of Scientific Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka, 567-0047, Japan., Sun J; Department of Pharmaceutical Science, University of South Florida, Tampa, Florida, 33612, USA., Ohkanda J; Academic Assembly, Institute of Agriculture, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano, 399-4598, Japan.
Jazyk: angličtina
Zdroj: Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2019 Oct 22; Vol. 25 (59), pp. 13531-13536. Date of Electronic Publication: 2019 Sep 09.
DOI: 10.1002/chem.201903129
Abstrakt: Unusual lipid modification of K-Ras makes Ras-directed cancer therapy a challenging task. Aiming to disrupt electrostatic-driven protein-protein interactions (PPIs) of K-Ras with FTase and GGTase I, a series of bivalent dual inhibitors that recognize the active pocket and the common acidic surface of FTase and GGTase I were designed. The structure-activity-relationship study resulted in 8 b, in which a biphenyl-based peptidomimetic FTI-277 was attached to a guanidyl-containing gallate moiety through an alkyl linker. Cell-based evaluation demonstrated that 8 b exhibited substantial inhibition of K-Ras processing without apparent interference with Rap-1A processing. Fluorescent imaging showed that 8 b disrupts localization of K-Ras to the plasma membrane and impairs interaction with c-Raf, whereas only FTI-277 was found to be inactive. These results suggest that targeting the PPI interface of K-Ras may provide an alternative method of inhibiting K-Ras.
(© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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