In vivo efficacy of natural product-inspired irreversible kinase inhibitors.
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.
Barluenga
Sofia
S
Institut de Science et Ingénierie Supramoléculaires (ISIS-UMR 7006), Université de Strasbourg-CNRS, 8 allée Gaspard Monge, 67000 Strasbourg, France.
Jogireddy
Rajamalleswaramma
R
Koripelly
Girish K
GK
Winssinger
Nicolas
N
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D020128:Inhibitory Concentration 50; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007783:Lactones / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011897:Random Allocation; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D007783:Lactones; D047428:Protein Kinase Inhibitors; D020797:Receptor, Platelet-Derived Growth Factor beta; D040281:Vascular Endothelial Growth Factor Receptor-1