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<p>Overcoming multidrug resistance (MDR) remains a critical challenge in non-small-cell lung cancer (NSCLC) therapy, particularly in cases driven by EGFR mutations and P-gp1 overexpression. This study aimed to design and synthesize Osimertinib (OSB) analogs (<b>14a–14m</b>) as dual inhibitors of EGFR and P-gp1, and optimize their activity, selectivity, and pharmacokinetics. Among these, compounds <b>14g</b> and <b>14l</b> emerged as potent candidates, demonstrating superior cytotoxicity against EGFR-mutant and Paclitaxel-resistant H1975_PTXR cells, with compound <b>14l</b> achieving the lowest IC₅₀ values and strong EGFR kinase inhibition (IC₅₀ = 50.58 ± 3.87&#xa0;nM). Mechanistic studies revealed that <b>14l</b> modulated P-gp1 ATPase activity, disrupted survival pathways (p-Akt and p-Erk2), and induced apoptosis through DNA fragmentation and mitochondrial disruption. In silico ADME analyses confirmed its favorable pharmacokinetic profile, including high bioavailability and reduced P-gp1 substrate potential. Docking studies highlighted <b>14l</b>’s high binding affinity for both EGFR (-9.81&#xa0;kcal/mol) and P-gp1 (-9.63&#xa0;kcal/mol)), further supporting its dual-targeting capability. In vivo studies demonstrated the efficacy and safety of <b>14l</b> in a multidrug-resistant NSCLC mouse model. Compound <b>14l</b> effectively inhibited tumor growth while maintaining minimal toxicity, as evidenced by stable body weights (24.1 ± 1.0&#xa0;g by Day 59). In contrast, the vehicle group exhibited significant weight loss due to tumor burden, while OSB-treated mice maintained stable weights (23.5 ± 1.0&#xa0;g). These findings underscore <b>14l’</b>s therapeutic potential as a dual EGFR and P-gp1 inhibitor, offering a promising strategy for overcoming MDR in NSCLC with robust efficacy and favorable safety profile.</p>

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Design and synthesis of novel Osimertinib analogs for dual EGFR and P-glycoprotein 1 inhibition targeting multidrug resistance in non-small cell lung cancer: In vitro and in vivo evaluation

  • 期刊论文

  • 发表日期：

    2025年9月11日

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  • Harikrishna Akkapelli,
  • Vidya Sagar Jerra,
  • Appaji Dokala,
  • Sudip Mandal

摘要

Overcoming multidrug resistance (MDR) remains a critical challenge in non-small-cell lung cancer (NSCLC) therapy, particularly in cases driven by EGFR mutations and P-gp1 overexpression. This study aimed to design and synthesize Osimertinib (OSB) analogs (14a–14m) as dual inhibitors of EGFR and P-gp1, and optimize their activity, selectivity, and pharmacokinetics. Among these, compounds 14g and 14l emerged as potent candidates, demonstrating superior cytotoxicity against EGFR-mutant and Paclitaxel-resistant H1975_PTXR cells, with compound 14l achieving the lowest IC₅₀ values and strong EGFR kinase inhibition (IC₅₀ = 50.58 ± 3.87 nM). Mechanistic studies revealed that 14l modulated P-gp1 ATPase activity, disrupted survival pathways (p-Akt and p-Erk2), and induced apoptosis through DNA fragmentation and mitochondrial disruption. In silico ADME analyses confirmed its favorable pharmacokinetic profile, including high bioavailability and reduced P-gp1 substrate potential. Docking studies highlighted 14l’s high binding affinity for both EGFR (-9.81 kcal/mol) and P-gp1 (-9.63 kcal/mol)), further supporting its dual-targeting capability. In vivo studies demonstrated the efficacy and safety of 14l in a multidrug-resistant NSCLC mouse model. Compound 14l effectively inhibited tumor growth while maintaining minimal toxicity, as evidenced by stable body weights (24.1 ± 1.0 g by Day 59). In contrast, the vehicle group exhibited significant weight loss due to tumor burden, while OSB-treated mice maintained stable weights (23.5 ± 1.0 g). These findings underscore 14l’s therapeutic potential as a dual EGFR and P-gp1 inhibitor, offering a promising strategy for overcoming MDR in NSCLC with robust efficacy and favorable safety profile.