21.2

Quinazoline-Based EGFR Kinase Inhibitors

Quinazolines are the heterocyclic scaffolds in which nitrogen atoms are present as a

part of their heterocyclic ring system. Chemically they are basic in nature and

possess a wide range of medicinal properties such as anticancer (Kumar et al.

2017; Molina-Pinelo et al. 2014), antitubercular, anti-inflammatory and antimicro-

bial activities. The quinazoline derivatives were found to inhibit the tyrosine kinase

domain of EGFR (Stuckey et al. 2015).

In the first decade of the century, gefitinib and erlotinib were discovered as

anticancer drugs and were approved by the FDA in the years 2003 and 2004,

respectively, for NSCLC. These molecules bind either reversibly to the intracellular

catalytic domain of the receptor and competitively inhibit the binding of adenosine

triphosphate. Occupation of the catalytic domain of EGFR by the inhibitors

reversibly/irreversibly inhibits phosphorylation and blocks the downstream signal-

ling and oncogenic effects associated with EGFR activation. Both drugs were

quinazoline derivatives in which substitution at different anilo derivatives was

done at position 4. The discovery of these compounds unfolded new and hopeful

4-anilinoquinazoline compounds in later years such as lapatinib, vandetanib, afatinib

and dacomitinib. The structures of these compounds are given in Fig. 21.1. As a

molecular targeting approach, EGFR is an auspicious target for cancer therapy.

Substitution of amino acid in exon 21 (i.e. L858R) and an in-frame deletion in

exon 19 are two typically perceived driver mutations in EGFR (Bhatia et al. 2020).

Fig. 21.1 FDA-approved quinazoline-based EGFR inhibitors as anticancer agents

21

EGFR-Targeted Quinazoline Clubbed Heterocycles as Anticancer Agents

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