(EP), β-cellulin (BTC), heparin-binding EGF (HB-EGF), and epiregulin (EPR)
[17, 18], and the main signaling pathways triggered by EGFR activation are PI3K/
AKT and MAPK and indirectly IL-6-mediated STAT activation [19, 20].
Deregulation of EGFR activity is associated with more aggressive epidermal
tumors, e.g., lungs, pancreas, breast, colon, and head and neck, and with poor
prognosis [21, 22], usually as a consequence of receptor overexpression, ligand
overproduction, and/or constitutive receptor activation due to point mutations or
other genetic alterations [23–27].
In this context, scientific efforts were extensively dedicated to enable the pharmacologic modulation of EGFR activity through the inhibition of its catalytic
domain with small molecular weight TKIs. Subsequent approval of several drugs
from this class by FDA demonstrated their clinical efficacy in different tumor types
[28]. However, challenges for the near future of this therapeutic strategy have also
emerged, as discussed throughout this chapter.
2.1 FDA-Approved EGFR Inhibitors
Currently six small molecular weight TKI drugs (1–6) are approved by FDA for
treating patients with tumors related to EGFR-deregulated activity (Fig. 2)
[7, 10]. Gefitinib (1; ZD1819; Iressa™; AstraZeneca), erlotinib (2; CP-258,774;
Tarceva™; Roche), and afatinib (5; BIBW2992; Giotrif™; Boehringer Ingelheim)
are approved by FDA for treatment of patients with non-small cell lung cancer
(NSCLC). In late 2015, osimertinib (6; AZD9291; Tagrisso™; AstraZeneca) was
approved as breakthrough therapy to treat NSCLC with no clinical benefits from
prior EGFR TKIs [29].
Lapatinib (3, GW572016; Tykerb™; GlaxoSmithKline) has as a primary indication for the treatment of breast cancer patients with HER-2 overexpression and with
no response to first choice drugs. In turn, vandetanib (4, ZD6474; Caprelsa™;
AstraZeneca) is approved to treat medullary thyroid cancer [30–32].
The 4-anilinoquinazoline moiety has been extensively explored for the last
decades in TKI drug discovery projects, especially for EGFR inhibition [33]. Noticeably, five of six approved EGFR TKI drugs have in common this privileged scaffold
in their chemical structure (Fig. 2).
2.2 Development of 4-Anilinoquinazolines as EGFR
Inhibitors
The history of the development of 4-anilinoquinazoline derivatives as EGFR inhibitors begins in the 1990s during research efforts undertaken at Zeneca Pharmaceuticals. Through a virtual screening approach using Zeneca Company Compound
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
159
[17, 18], and the main signaling pathways triggered by EGFR activation are PI3K/
AKT and MAPK and indirectly IL-6-mediated STAT activation [19, 20].
Deregulation of EGFR activity is associated with more aggressive epidermal
tumors, e.g., lungs, pancreas, breast, colon, and head and neck, and with poor
prognosis [21, 22], usually as a consequence of receptor overexpression, ligand
overproduction, and/or constitutive receptor activation due to point mutations or
other genetic alterations [23–27].
In this context, scientific efforts were extensively dedicated to enable the pharmacologic modulation of EGFR activity through the inhibition of its catalytic
domain with small molecular weight TKIs. Subsequent approval of several drugs
from this class by FDA demonstrated their clinical efficacy in different tumor types
[28]. However, challenges for the near future of this therapeutic strategy have also
emerged, as discussed throughout this chapter.
2.1 FDA-Approved EGFR Inhibitors
Currently six small molecular weight TKI drugs (1–6) are approved by FDA for
treating patients with tumors related to EGFR-deregulated activity (Fig. 2)
[7, 10]. Gefitinib (1; ZD1819; Iressa™; AstraZeneca), erlotinib (2; CP-258,774;
Tarceva™; Roche), and afatinib (5; BIBW2992; Giotrif™; Boehringer Ingelheim)
are approved by FDA for treatment of patients with non-small cell lung cancer
(NSCLC). In late 2015, osimertinib (6; AZD9291; Tagrisso™; AstraZeneca) was
approved as breakthrough therapy to treat NSCLC with no clinical benefits from
prior EGFR TKIs [29].
Lapatinib (3, GW572016; Tykerb™; GlaxoSmithKline) has as a primary indication for the treatment of breast cancer patients with HER-2 overexpression and with
no response to first choice drugs. In turn, vandetanib (4, ZD6474; Caprelsa™;
AstraZeneca) is approved to treat medullary thyroid cancer [30–32].
The 4-anilinoquinazoline moiety has been extensively explored for the last
decades in TKI drug discovery projects, especially for EGFR inhibition [33]. Noticeably, five of six approved EGFR TKI drugs have in common this privileged scaffold
in their chemical structure (Fig. 2).
2.2 Development of 4-Anilinoquinazolines as EGFR
Inhibitors
The history of the development of 4-anilinoquinazoline derivatives as EGFR inhibitors begins in the 1990s during research efforts undertaken at Zeneca Pharmaceuticals. Through a virtual screening approach using Zeneca Company Compound
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
159