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In Vivo Efficacy of Natural Product‐Inspired Irreversible Kinase Inhibitors
Author(s) -
Barluenga Sofia,
Jogireddy Rajamalleswaramma,
Koripelly Girish K.,
Winssinger Nicolas
Publication year - 2010
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201000205
Subject(s) - pharmacophore , sunitinib , in vivo , chemistry , natural product , moiety , kinome , in vitro , cancer research , pharmacology , kinase , biochemistry , stereochemistry , biology , medicine , cancer , microbiology and biotechnology
Hypothemycin and related resorcylic acid lactones (RAL) bearing a cis ‐enone moiety have emerged as an alternative pharmacophore to heterocyclic motifs for kinase inhibition, and are endowed with a unique selectivity filter based on the irreversible reaction with a subset of the kinome bearing a suitably positioned cysteine residue. Two prototypical examples of “edited” RAL were evaluated for antitumoral, antimetastatic and antiangiogenic efficacy in an orthotopic murine renal cell carcinoma (RENCA) model. Both compounds ( 3 and 5 ) are good inhibitors of VEGFRs in vitro, and inhibited tumor growth in vivo with comparable efficacy to sunitinib, an FDA‐approved VEGFRs inhibitor. Compound 3 promoted lung metastasis to a similar extent as sunitinib, while compound 5 strongly inhibited lung metastasis. This study attests to the potential of irreversible kinase inhibitors and molecular editing of natural pharmacophores and provides encouraging results to a clinically significant problem.