Description
Overactivity of epidermal growth factor receptor (EGFR) tyrosine kinase activity has been associated with a number of cancers.
1 CL 387,785 is a potent, irreversible inhibitor of EGFR kinase activity (IC
50 = 370 pM).
2 It blocks EGF-stimulated autophosphorylation of receptors in cells (IC
50 = 5 nM) and halts cell cycling in cells that overexpress EGFR or c-ErbB2 (IC
50s = 31-125 nM).
2 CL 387,785 profoundly blocks the growth of EGFR-overexpressing tumors in nude mice when given orally at 80 mg/kg/day for 10 days.
2
Uses
Irreversibly inhibits EGF-stimulated autophosphorylation of tyrosine residues in the epidermal growth factor receptor (EGFR) in vivo (IC50=250-490pM) and blocks EGF-mediated growth.
Definition
ChEBI: A member of the class of quinazolines that is 4,6-diaminoquinazoine in which the one of the hydrogens attached to the amino group at position 4 has been replaced by a m-bromophenyl group while one of the hydrogens attached to the amino group a
position 6 has been replaced by a but-2-ynoyl group.
in vitro
cl-387785 covalently bound to egfr. it also specifically inhibited kinase activity of the protein, blocked egf-stimulated autophosphorylation of the receptor in cells, inhibited cell proliferation primarily in a cytostatic manner in cell lines that overexpress egf-r or c-erbb-2 [1].
in vivo
the effects of cl-387785 on tumor growth were assessed in human tumor xenografts implanted s.c. in the flanks of nude mice. cl-387785 inhibited the growth of tumors derived from a431 cells when the drug was administered i.p. or p.o.. inhibitory effects were observed within 7 days after the onset of therapy. no efficacy was observed with cl-387785 in tumors derived from cell lines that did not overexpress egf-r, including the human breast carcinoma mda-mb-435 [1].
References
[1] discafani cm, carroll ml, floyd mb jr, hollander ij, husain z, johnson bd, kitchen d, may mk, malo ms, minnick aa jr, nilakantan r, shen r, wang yf, wissner a, greenberger lm. irreversible inhibition of epidermal growth factor receptor tyrosine kinase with in vivo activity by n-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (cl-387,785). biochem pharmacol. 1999 apr 15;57(8):917-25.
