Journal
CHEMBIOCHEM
Volume 11, Issue 12, Pages 1692-1699Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201000205
Keywords
antitumor agents; inhibitors; kinetics; lactones; natural products
Funding
- Agence National de la Recherche (ANR)
- Conectus
- Institut Universitaire de France (IUF)
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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
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