NEP010, a novel compound with minor structural modification from afatinib, exhibited significantly improved antitumor activity

Non-small-cell lung cancer (NSCLC) has advanced in many areas, including classification, diagnosis, and therapy. After extensive scientific investigations, NSCLC is classified into subclasses on the basis of the specific kinase mutation. The most common mutation is the epidermal growth factor receptor (EGFR) somatic mutation, which has promoted the development of several novel drugs (Tyrosine kinase inhibitors -TKIs) (Pecci et al., 2022).

Besides erlotinib, gefitinib, dacomitinib, mobocertinib, and osimertinib, afatinib is one of the therapeutic compounds recommended by the American National Comprehensive Cancer Network (NCCN) guideline to treat patients with non-small cell lung cancer (NSCLC) having EGFR mutation (Koulouris et al., 2022; Moosavi and Polineni, 2022; Nematpour et al., 2022). Several drugs were designed to inhibit EGFR. However, clinical trials revealed significant diversity in response rates across different NSCLC patients. For example, reversible inhibitors such as erlotinib and gefitinib showed weak efficacy in patients with L861Q mutation, osimertinib possesses the risk to induce QTc prolongation, dacomotinib could interact with proton pump inhibitors, and afatinib showed interaction with p-glycoprotein. Therefore, even though several TKIs which focused on EGFR mutation are available in clinical practice, a series of novel compounds are still required to fulfill the present therapeutic demands (Cooper et al., 2022; Nematpour et al., 2022; Shen et al., 2022; Shi et al., 2022; Wang et al., 2022).

Optimizing the structure of a compound is one approach to enhance its pharmacodynamic properties. Furthermore, minor structure modification may maximally restore some particular bioactivity of the basic compounds. According to the review published by U.S. Food and Drug Administration (FDA) (Leighton, 2013), afatinib showed significant inhibition on EGFR, but also provided some important aspects of further optimization to improve the antitumor activity.

Thus, in this study, afatinib was selected for structural modification. We modified the structure of afatinib while preserving the covalent binding sites (Fig. 1) (Kannan et al., 2017) to prevent the down regulation of the irreversible bonding activity.

To validate the success of the modification, we focused on the preclinical evaluation of NEP010 to evaluate the modified antitumor efficacy of NEP010. Because afatinib was the original drug, it was used as the positive control of the study. The xenograft models with various EGFR mutant tumors, including one rare mutant genotype tumor, were established to investigate the potent therapeutic advantage of NEP010. Furthermore, a kinase inhibition test and some essential pharmacokinetic tests were performed to elucidate the potential mechanisms underlying the improvement of drug efficacy of NEP010 compare with that of afatinib.

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