2. Academic Validation
  3. Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant Non-Small-Cell Lung Cancer

Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant Non-Small-Cell Lung Cancer

  • J Med Chem. 2023 Oct 23. doi: 10.1021/acs.jmedchem.3c01400.
Tizhi Wu 1,  Bin Yu 1,  Yifan Xu 1,  Zekun Du 1,  Zhiming Zhang 1,  Yuxiao Wang 1,  Haoming Chen 1,  Li Ao Zhang 1,  Rui Chen 1,  Feihai Ma 1,  Weihong Gong 1,  Sixian Yu 1,  Zhixia Qiu 1,  Hongxi Wu 1,  Xi Xu 1,  Jubo Wang 1,  Zhiyu Li 1,  Jinlei Bian 1
Affiliations

Affiliation

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. China.
PMID: 37870244 DOI: 10.1021/acs.jmedchem.3c01400
Abstract

Effectiveness of epidermal growth factor receptor (EGFR) inhibitors, including Osimertinib, for treating non-small-cell lung Cancer (NSCLC) is limited due to the continuous emergence of drug resistance. Hence, it is urgent to develop new therapeutic approaches. CDK9, a key regulator of RNA transcription, has emerged as a promising target for the development of antitumor drugs due to its crucial role in modulating the levels of antiapoptotic protein Mcl-1. Herein, we present the synthesis, optimization, and evaluation of selective CDK9 inhibitors with a macrocyclic scaffold that effectively suppresses the growth of NSCLC cells. Notably, compound Z11, a potent CDK9 Inhibitor (IC50 = 3.20 nM) with good kinase selectivity, significantly inhibits cell proliferation and colony formation and induces Apoptosis in Osimertinib-resistant H1975 cells. Furthermore, Z11 demonstrates a significant suppression of tumor growth in six patient-derived organoids, including three organoids resistant to Osimertinib. Overall, Z11 served as a promising macrocycle-based CDK9 Inhibitor for treating Osimertinib-resistant NSCLC.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149641
    CDK9 抑制剂
    CDK
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