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

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.