2. Academic Validation
  3. A novel kinase inhibitor, LZT-106, downregulates Mcl-1 and sensitizes colorectal cancer cells to BH3 mimetic ABT-199 by targeting CDK9 and GSK-3β signaling

A novel kinase inhibitor, LZT-106, downregulates Mcl-1 and sensitizes colorectal cancer cells to BH3 mimetic ABT-199 by targeting CDK9 and GSK-3β signaling

  • Cancer Lett. 2021 Feb 1;498:31-41. doi: 10.1016/j.canlet.2020.10.001.
Zhou Yu 1,  Jiaying Du 1,  Yue Zhao 1,  Yuan Gao 2,  Yongxu Li 1,  Kai Zhao 3,  Na Lu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
  • 2 Pharmaceutical Animal Experimental Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
  • 3 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China. Electronic address: cpuzhaokai@163.com.
  • 4 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China. Electronic address: nalu@cpu.edu.cn.
PMID: 33129955 DOI: 10.1016/j.canlet.2020.10.001
Abstract

Colorectal Cancer (CRC) is one of the most common malignancies worldwide and is associated with poor prognosis and high mortality. Despite advances in treatment with chemotherapy, CRC remains a major cause of drug resistance-related Cancer deaths. One of the main reasons for such resistance is dysregulation of Mcl-1 expression. In this study, we identified LZT-106 as a novel kinase inhibitor that was able to bind to CDK9 with potent inhibitory ability, and indirectly regulate the expression of Mcl-1. However, different regulatory profiles were observed between LZT-106 and the well-studied CDK9 Inhibitor flavopiridol with regards to Mcl-1 inhibition. Via Western blotting, Real-Time PCR and immunoprecipitation, we confirmed that LZT-106 was also able to target GSK-3β signaling and facilitate the degradation of Mcl-1. And LZT-106 was shown to synergize with ABT-199 to induce Apoptosis even in the RKO cell line that overexpressed Mcl-1. Finally, LZT-106 significantly inhibited tumor growth in a xenograft mouse model with minimal toxicity. Overall, our findings suggest that LZT-106 is a promising candidate drug for the treatment of patients with CRC.

Keywords

ABT-199; Apoptosis; Colorectal cancer; GSK-3β; Mcl-1.

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