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- Title
Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors.
- Authors
Carlomagno, Francesca; Guida, Teresa; Anaganti, Suresh; Vecchio, Giancarlo; Fusco, Alfredo; Ryan, Anderson J; Billaud, Marc; Santoro, Massimo
- Abstract
We have recently demonstrated that the pyrazolopyrimidines PP1 and PP2 and the 4-anilinoquinazoline ZD6474 display a strong inhibitory activity (IC50?100?nM) towards constitutively active oncogenic RET kinases. Here, we show that most oncogenic MEN2-associated RET kinase mutants are highly susceptible to PP1, PP2 and ZD6474 inhibition. In contrast, MEN2-associated swap of bulky hydrophobic leucine or methionine residues for valine 804 in the RET kinase domain causes resistance to the three compounds. Substitution of valine 804 with the small amino- acid glycine renders the RET kinase even more susceptible to inhibition (ZD6474 IC50: 20?nM) than the wild-type kinase. Our data identify valine 804 of RET as a structural determinant mediating resistance to pyrazolopyrimidines and 4-anilinoquinazolines.Oncogene (2004) 23, 6056-6063. doi:10.1038/sj.onc.1207810 Published online 7 June 2004
- Subjects
PLANT fibers; TEXTILE fibers; AMINO acids; METHIONINE; ACETIC acid; GLYCINE
- Publication
Oncogene, 2004, Vol 23, Issue 36, p6056
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1207810