Urea derivatives of STI571 as inhibitors of Bcr-Abl and PDGFR kinases.

Posted by rob on October 28, 2004 under Uncategorized | Be the First to Comment

Bioorg Med Chem Lett. 2004 Dec 6; 14(23): 5793-7
Manley PW, Breitenstein W, Brüggen J, Cowan-Jacob SW, Furet P, Mestan J, Meyer T

The constitutively active Abl kinase activity of the Bcr-Abl oncoprotein is causative for chronic myelogenous leukemia. Urea derivatives, structurally related to the therapeutic agent STI571, have been identified, which potently inhibit the tyrosine kinase activity of recombinant Abl. In particular a dimethylamino-aniline derivative (18) inhibited c-Abl transphosphorylation with an IC(50) value of 56nM. Although this activity was not translated into cellular activity against the constitutively activated oncogenic Bcr-Abl, a number of compounds from this series potently inhibited cellular PDGFR autophosphorylation. It was also possible to differentiate between c-Abl and PDGFR kinase inhibition, with compound 22 being selective towards Abl and 23 selective for PDGFR.

http://www.hubmed.org/display.cgi?issn=0960894X&uids=15501042