Uses
PF299804 is a potent, irreversible pan-ErbB inhibitor against ErbB1, ErbB2 and ErbB4 with IC50 of 6 nM, 45.7 nM and 73.7 nM, respectively.
Definition
ChEBI: A member of the class of quinazolines that is 7-methoxyquinazoline-4,6-diamine in which the amino group at position 4 is substituted by a 3-chloro-4-fluorophenyl group and the amino group at position 6 is substituted by an (E)-4-(piperidin
1-yl)but-2-enoyl group.
in vitro
dacomitinib reduced the phosphorylation of her2, egfr, her4, akt, anderkin the majority of sensitive lines. dacomitinib exerted its antiproliferative effect through a combined g0–g1 arrest and an induction of apoptosis. dacomitinib inhibited growth in several her2-amplified lines with de novo and acquired resistance to trastuzumab. dacomitinib maintained a high activity in lines with acquired resistance to lapatinib. this study identifies her2-amplified breast cancer lines as most sensitive to the antiproliferative effect of dacomitinib and provides a strong rationale for its clinical testing in her2-amplified breast cancers resistant to trastuzumab and lapatinib [1].
in vivo
to evaluate the in vivo efficacy of pf00299804, the authors generated xenografts in nu/nu mice using hcc827 gfp and hcc827 del/t790m cells and treated the mice with pf00299804. pf00299804 effectively inhibited the growth of hcc827 gfp xenografts. pf00299804 treatment was substantially more effective at inhibiting growth of this xenograft model than gefinitib. thus, these preclinical models suggest that pf00299804 may be quite effective against lung cancers that become resistant to gefitinib or erlotinib via acquisition of a t790m mutation in egfr [2].
References
[1] kalous o, conklin d, desai aj, o'brien na, ginther c, anderson l, cohen dj, britten cd, taylor i, christensen jg, slamon dj, finn rs. dacomitinib (pf-00299804), an irreversible pan-her inhibitor, inhibits proliferation of her2-amplified breast cancer cell lines resistant to trastuzumab and lapatinib. mol cancer ther. 2012;11(9):1978-87.
[2] engelman ja, zejnullahu k, gale cm, lifshits e, gonzales aj, shimamura t, zhao f, vincent pw, naumov gn, bradner je, althaus iw, gandhi l, shapiro gi, nelson jm, heymach jv, meyerson m, wong kk, jfinne pa. pf00299804, an irreversible pan-erbb inhibitor, is effective in lung cancer models with egfr and erbb2 mutations that are resistant to gefitinib. cancer res. 2007;67(24):11924-32.
