| BIBW2992 is an irreversible inhibitor of ErbB family with IC50s of 0.5, 14 and 1 nM for epidermal growth factor receptor (EGFR) (ErbB1/HER1), HER2 and HER4 kinases. BIBW2992 inhibits EGF-induced EGFR phosphorylation and cellular proliferation in cell lines such as EGFR-overexpressing and HER2-expressing cell lines A431, NIH-3T3-HER2, NCI-N87 and BT-474. [1] In cell-free in vitro kinase assays, BIBW2992 also demonstrates potent activity against mutant forms of EGFR and HER2. In three NSCLC cell lines (H1666, H3255 and H1975), BIBW2992 potently inhibits EGFR phosphorylation in all three cell lines with IC50s of 7, 6 and 93 nM, respectively. Furthermore, BIBW2992 is shown to be more effective than erlotinib, gefitinib or lapatinib in inhibiting survival of lung cancer cell lines. [2] BIBW2992 also shows great activity in human pancreatic tumour cells. Of the seven human pancreatic tumor cell lines including Capan-1, PT-45, PANC-1, BxPC-3, MiaPaCa-2, AsPc-1, FA6 examined, BxPC-3 cells are the most sensitive cell line to treatment with BIBW2992 with an IC50 of 11 nM, and the growth of other human pancreatic tumor cells is inhibited by BIBW2992 with IC50s ranging from 0.37 to 1.37 μM.[3] Meanwhile, BIBW2992 is similar to gefitinib in potency for L858R EGFR with an IC50 of 0.7 nM, but approximately 100-fold more active against the gefitinib-resistant L858R/T790M EGFR double mutant with an IC50 of 99 nM. BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits survival of cancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib.[4] Oral BIBW2992 induces tumour regression in mice carrying EGFR-overexpressing and HER2-expressing A431 xenografts, in mice carrying EGFR-over-expressing and HER2-expressing MDA-MB-453 xenografts, and in NCI-N87 gastric and SKOV-3 ovarian models at plasma concentrations of 80-280 nM.[1] In vivo , BIBW2992 shows potent anti-tumour activity in the BxPC-3 human pancreatic xenograft model. Daily administration of 15 mg/kg BIBW2992 as a single agent to mice carrying established tumours significantly delays tumour growth with a T/C value of 18% and a tumour growth inhibition (TGI) value of 89%.[3] |
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