Overcoming resistance in non‐small‐cell lung cancer: A practical lesson for the medicinal chemist

: The introduction of tyrosine kinase inhibitors (TKIs) in the clinical management of oncological patients spread the light on the use of selective, rationally designed small molecules for the treatment of cancer. First-generation TKIs bared high response against these malignancies, although the unavoidable shadow of resistance limits their long-term efficacy. Non-small-cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, and it is the first cause of cancer deaths worldwide for men and women. Traditional chemotherapy is marginally effective against this form, and erlotinib and gefitinib were introduced as first-line treatments based on the observation that the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK), is mutated in several cases and, thus, represents a druggable target. EGFR-mutant and anaplastic lymphoma kinase (ALK)-positive patients are more responsive to these treatments, even if secondary mutations causing resistance soon emerged. The efforts of medicinal chemists are currently oriented toward the development of new generations of TKIs overcoming these obstacles. We here overview the novel strategies from the point of view of the medicinal chemist: the rational structure-based drug design that led to the development of irreversible and non-ATP-competitive inhibitors. Such improvements parallel the novel therapeutic strategies adopted in the clinic, which are also discussed.