Solid-phase synthesis and pharmacological evaluation of a library of peptidomimetics as potential farnesyltransferase inhibitors: an approach to new lead compounds

European Journal of Medicinal Chemistry
P GilleronJ-P Hénichart

Abstract

Oncogenic Ras proteins whose activation is farnesylation by farnesyltransferase have been seen as important targets for novel anticancer drugs. Inhibitors of this enzyme have already been developed as potential anti-cancer drugs, particularly by rational design based on the structure of the CA(1)A(2)X carboxyl terminus of Ras. Synthesis of a peptidomimetics library via solid-phase synthesis using the Multipin method is described here. The most active hits on cellular assays were resynthesized and enzymatic activity was measured. Compounds A1, A5 and A7 present significant activity on the isolated enzyme (IC(50)=117, 57.3 and 28.5 nM) and their molecular docking in the active site of the enzyme provides details on key interactions with the protein.

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Citations

Mar 1, 2013·MedChemComm·Joshua D Ochocki, Mark D Distefano
Jul 16, 2020·Advanced Pharmaceutical Bulletin·Saeed GhasemiJavid Shahbazi Mojarrad
Sep 20, 2007·Journal of Combinatorial Chemistry·Roland E DolleWei Zhang

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