Novel cyclin-dependent kinase 9 (CDK9) inhibitor with suppression of cancer stemness activity against non-small-cell lung cancer

• DOI: 10.1016/j.ejmech.2019.07.038
• Publication Date: 2019-07-25T15:37:43Z
• Authors: Xin Wang; Chenhua Yu; Cheng Wang; Yakun Ma; Tianqi Wang; Yao Li; Zhi Huang; Manqian Zhou; Peiqing Sun; Jianyu Zheng; Shengyong Yang; Yan Fan; Rong Xiang
• Keywords: 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

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.