Afatinib (BIBW 2992)

In July 2013, the US FDA approved afatinib (also referred to as BIBW- 2992), for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) and with tumors that have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution. Afatinib functions as an irreversible inhibitor by covalently binding directly to the ATP-binding site in the kinase domains of both EGFR(Cys 773) andHER2 (Cys 805;HER-2 is the preferred dimerization partner of EGFR) resulting in downregulation of EGFR signaling. Afatinib is a potent inhibitor of wild-type and mutant forms (L858R) of EGFR (IC_50s of 0.5 and 0.4 nM, respectively), and HER2 (IC₅₀=14 nM), but about 100-fold more active against the gefitinib resistant L858R– T790M EGFR double mutant, with an IC₅₀ of 10 nM. Consistent with its in vitro activity, afatinib induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib. A synthetic route to afatinib that employs the displacement of a phenylsulfonyl group to install the (S)-3-hydoxytetrahydrofuran ring and a modified Horner–Wadsworth–Emmons reaction with {[4-(3-chloro-4- phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-ylcarbamoyl]- methyl}-phosphonate and dimethylaminoacetaldehyde-hydrogen sulfite adduct to install the eneamide moiety, has been reported.

BIBW2992 (Afatinib, Tomtovok, Tovok) irreversibly inhibits EGFR/HER2 including EGFRwt, EGFRL858R, EGFRL858R/T790M and HER2 with IC50 of 0.5 nM, 0.4 nM, 10 nM and 14 nM, respectively.