Related Experiment Video

Updated: Jul 12, 2025

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
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Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant

Tizhi Wu1, Bin Yu1, Yifan Xu1

  • 1Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. China.

Journal of Medicinal Chemistry
|October 23, 2023
PubMed

Insights

New macrocycle-based CDK9 inhibitors show promise for treating drug-resistant non-small-cell lung cancer (NSCLC). Compound Z11 effectively inhibits tumor growth and induces apoptosis in Osimertinib-resistant NSCLC cells and patient-derived organoids.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Molecular Biology

Background:

  • Drug resistance to epidermal growth factor receptor (EGFR) inhibitors like Osimertinib limits non-small-cell lung cancer (NSCLC) treatment effectiveness.
  • Cyclin-dependent kinase 9 (CDK9) is a key regulator of RNA transcription and a potential therapeutic target due to its role in Mcl-1 modulation.

Purpose of the Study:

  • To synthesize and evaluate selective CDK9 inhibitors with a macrocyclic scaffold for treating drug-resistant NSCLC.
  • To assess the efficacy of these inhibitors in preclinical NSCLC models, including Osimertinib-resistant cell lines and patient-derived organoids.

Main Methods:

  • Synthesis and optimization of macrocyclic compounds targeting CDK9.
  • In vitro evaluation of CDK9 inhibitory activity and kinase selectivity.
  • Assessment of anti-proliferative and pro-apoptotic effects in NSCLC cell lines.
  • In vivo efficacy studies using patient-derived organoid models.

Main Results:

  • Compound Z11, a potent and selective CDK9 inhibitor (IC50 = 3.20 nM), was identified.
  • Z11 significantly inhibited proliferation and colony formation while inducing apoptosis in Osimertinib-resistant H1975 NSCLC cells.
  • Z11 demonstrated significant tumor growth suppression in patient-derived organoids, including those resistant to Osimertinib.

Conclusions:

  • Macrocycle-based CDK9 inhibitors, exemplified by Z11, represent a promising therapeutic strategy for Osimertinib-resistant NSCLC.
  • Targeting CDK9 offers a viable approach to overcome drug resistance in non-small-cell lung cancer.

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