Novel cyclin-dependent kinase 9 (CDK9) inhibitor with suppression of cancer stemness activity against non-small-cell lung cancer
0301 basic medicine
0303 health sciences
Lung Neoplasms
Dose-Response Relationship, Drug
Molecular Structure
Antineoplastic Agents
Apoptosis
Cyclin-Dependent Kinase 9
3. Good health
Structure-Activity Relationship
03 medical and health sciences
Isothiocyanates
Carcinoma, Non-Small-Cell Lung
Sulfoxides
Tumor Cells, Cultured
Humans
Drug Screening Assays, Antitumor
Protein Kinase Inhibitors
Cell Proliferation
DOI:
10.1016/j.ejmech.2019.07.038
Publication Date:
2019-07-25T15:37:43Z
AUTHORS (13)
ABSTRACT
A series of novel, highly potent, selective CDK9 inhibitors with cancer stem cells (CSCs) inhibition activity were designed and synthesized for non-small-cell lung cancer (NSCLC) therapy. Structure-activity relationship analysis based on enzymatic and cellular activities led to the discovery of a promising inhibitor 21e. 21e potently inhibited CDK9 with IC50 value of 11 nM and suppressed the stemness properties of NSCLC effectively. It could decrease the stemness phenotypes of NSCLC cells, including tumor sphere formation, side-population and stemness markers abundance. 21e displayed good selectivity over the CDK family kinases and kinase profiling assay against 381 kinases. In addition, 21e inhibited cell proliferation, colony-formation, and cell cycle progression and induced apoptosis in NSCLC. In H1299 xenograft mouse model, a once-daily dose of compound 21e at 20 mg/kg significantly suppressed the tumor growth without obvious toxicity. Studies of mechanisms of action indicated that 21e efficiently inhibited CDK9 signaling pathway and stemness both in vitro and in vivo. Collectively, 21e as a novel CDK9 inhibitor with CSCs inhibition properties could be a promising agent for the treatment of NSCLC.
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