Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant Non-Small-Cell Lung Cancer.
Tizhi WuBin YuYifan XuZekun DuZhiming ZhangYuxiao WangHaoming ChenLi Ao ZhangRui ChenFeihai MaWeihong GongSixian YuZhixia QiuHongxi WuXi XuJubo WangZhiyu LiJinlei BianPublished in: Journal of medicinal chemistry (2023)
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 (IC 50 = 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.
Keyphrases
- epidermal growth factor receptor
- advanced non small cell lung cancer
- small cell lung cancer
- cell cycle
- tyrosine kinase
- cell proliferation
- induced apoptosis
- cell cycle arrest
- signaling pathway
- randomized controlled trial
- systematic review
- small molecule
- oxidative stress
- brain metastases
- anti inflammatory
- photodynamic therapy
- cell death
- high throughput
- combination therapy
- smoking cessation
- induced pluripotent stem cells
- amino acid
- replacement therapy
- drug induced