2. Academic Validation
  3. β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K

β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K

  • Nat Prod Bioprospect. 2024 Jan 3;14(1):3. doi: 10.1007/s13659-023-00422-y.
Shiyun Nie # 1,  Lizhong Chang # 1,  Ying Huang 1,  Heyang Zhou 1,  Qianqing Yang 1,  Lingmei Kong 2,  Yan Li 3
Affiliations

Affiliations

  • 1 Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China.
  • 2 Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China. konglingmei@ynu.edu.cn.
  • 3 Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China. yan.li@ynu.edu.cn.
  • # Contributed equally.
PMID: 38169019 DOI: 10.1007/s13659-023-00422-y
Abstract

Phosphoinositide 3-kinase (PI3Ks) are lipid kinases widely involved in cell proliferation, metastasis and differentiation. Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers (CRCs). In this study, we identified isopropyl 9-ethyl-1-(naphthalen-1-yl)-9 H-pyrido[3,4-b] indole-3-carboxylate (Z86), as a novel PI3Kα Inhibitor with the IC50 value of 4.28 µM. The binding of Z86 to PI3Kα was further confirmed with DARTS and CETSA assay. Immunofluorescence analysis and western blotting data demonstrated that Z86 effectively attenuated PI3K/Akt pathway. Z86 caused dramatic proliferation inhibition of CRCs through G0/G1 cycle arrest rather than Apoptosis induction. Besides, the migration of CRCs was also relieved by Z86. The present study not only identified Z86 as a novel PI3Kα Inhibitor with potent inhibitory efficiency on PI3K-mediated CRCs growth and migration, but also elucidated a reasonable molecular mechanism of Z86 in the Wnt signaling pathway inhibition.

Keywords

Cell cycle arrest; Colorectal cancer; PI3K; Proliferation; Z86.

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