Fourth-Generation Allosteric EGFR Tyrosine Kinase Inhibitors to Combat the Drug Resistance Associated with Non-small Cell Lung Cancer (NSCLC)

Non-small cell lung cancer (NSCLC) is the leading cause of mortality in oncology, and EGFR-TK plays a critical role in this disease. As a result, EGFR-TK is a viable target for therapeutic development in NSCLC. The T790M EGFR TK mutation was resistant to both first-generation and second-generation (selectivity issue) EGFR-TK inhibitors. Although third-generation drugs (Osimertinib) can overcome the EGFR T790M mutation, a recent C797S mutation makes these agents ineffective against it. All of the currently available EGFR kinase inhibitors target the kinase’s highly conserved ATP site, underlining the need for therapeutics with a different mechanism of action (allosteric binding). EAI001, EAI045, JBJ-04-125-02, DDC4002 and a series of small compounds (fourth generation) having an affinity for the EGFR allosteric site have been discovered and are currently being investigated. To overcome EGFR T790M/C797S resistance, allosteric mutant-selective fourth-generation EGFR inhibitors look to be a promising treatment approach. This chapter discusses the advantages of blocking allosteric sites in the EGFR-TK receptor domains and compares novel fourth-generation EGFR-TKIs for overcoming drug treatment resistance.