Chemical Reviews pubs.acs.
org/CR Review
Figure 35. First- and second-generation inhibitors of EGFR. First-generation inhibitors gefitinib, erlotinib, and icotinib. Second-generation
inhibitors afatinib and dacomitinib.
Figure 36. Binding mode of gefitinib in EGFR with L858R, exon19 region, and T790M highlighted (PDB code 2ITY).
mutations which resulted in resistance to type I inhibitors. ways which drive pro-proliferative and survival signaling.226
However, alternative mechanisms of resistance were observed After disappointing early clinical results using EGFR inhibitors
to type II agents including H1094Y and L1195V which may in broad NSCLC patient populations, it was shown that tumor
impact through a steric clash with these agents (Figure 34).225 growth was driven by EGFR activating mutations such as an
Therefore, further clinical data will be required on cMET exon 19 deletion, or the L858R mutation, which render the
inhibitors to understand the relevant vulnerability of type I and receptor constitutively activated.227 Therefore, abrogation of
type II templates and how this may impact the optimal clinical activated EGFR signaling using small molecule inhibitors
strategy. resulted in inhibition of tumor growth through the prevention
of signaling, and therefore reduced oncogenic drive.
3.11. EGFR
Typically now referred to as “first-generation” EGFR
Ligand induced activation of the epidermal growth factor inhibitors, gefitinib and erlotinib (Figure 35) were approved
receptor (EGFR) promotes activation of downstream path- by the FDA in NSCLC patients with activating mutations in
AB https://dx.doi.org/10.1021/acs.chemrev.0c00383
Chem. Rev. XXXX, XXX, XXX−XXX
