An irreversible inhibitor of EGFR kinase activity
Description:
IC50: 370 pM
The EGFR is a 170-kDa protein that contains an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. EGF-R is hyperactivated in numerous tumors including those derived from the lung, brain, bladder, prostate, head, and neck. It has been shown previously that 4-anilino quinazolines compete with the ability of ATP binding the EGFR, inhibit EGF-stimulated autophosphorylation of tyrosine residues in EGFR, and block EGF-mediated growth. CL-387785 is an irreversible inhibiter of EGFR.
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].
Clinical trial: Up to now, CL-387785 is still in the preclinical development stage.
Reference:
[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.
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