Abstract 6995: Novel 4,6-disubstituted-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidines as dual mEGFR/AURK inhibitors for non-small cell lung cancer

Abstract The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) constitute the recommended therapy for non-small cell lung cancer (NSCLC) expressing mutant epidermal growth factor receptor (mEGFR). Resistance to first-generation EGFR-TKIs was addressed by osimertinib, an irreversible EGFR-TKI. However, newer mutations and redundant signaling pathways continue to drive resistance to osimertinib in mEGFR+ NSCLC. There are currently no viable EGFR-mediated treatments for osimertinib-resistant NSCLC. The aurora kinases (AURKA, AURKB) are mitotic kinases involved in centrosome maturation and separation during mitosis and can contribute to tumorigenesis. The AURK inhibitors have resensitized osimertinib-resistant mEGFR+ NSCLC cells when combined with osimertinib. Thus, dual mEGFR/AURK inhibition provides a unique approach for mEGFR+NSCLC. Kurup et al. previously investigated 4-substituted-7H-pyrrolo[2,3-d]pyrimidines as dual mEGFR/AURK inhibitors. Compounds 1-8 were developed as 4,6-disubstituted-7H-pyrrolo[2,3-d]pyrimidines to determine their effects as dual mEGFR/AURK inhibitors. The design, synthesis, and evaluation of compounds 1-8 will be presented and discussed. The anticancer effects of dual mEGFR and AURK inhibition in osimertinib-resistant mEGFR+ NSCLC cells will also be presented. Citation Format: Sonali Kurup, QiQi Hu, Kexin Zheng, Samantha Satawa, Felix Amissah, Erika Lisabeth. Novel 4,6-disubstituted-7H-pyrrolo[2,3-d]pyrimidines as dual mEGFR/AURK inhibitors for non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6995.