2. Academic Validation
  3. Design, synthesis and biological evaluation of ring A modified 11-keto-boswellic acid derivatives as Pin1 inhibitors with remarkable anti-prostate cancer activity

Design, synthesis and biological evaluation of ring A modified 11-keto-boswellic acid derivatives as Pin1 inhibitors with remarkable anti-prostate cancer activity

  • Bioorg Med Chem Lett. 2018 Oct 15;28(19):3187-3193. doi: 10.1016/j.bmcl.2018.08.021.
Min Huang 1,  Aihua Li 1,  Feng Zhao 1,  Xiaorui Xie 2,  Kun Li 1,  Yongkui Jing 2,  Dan Liu 3,  Linxiang Zhao 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: sammyld@163.com.
  • 4 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: linxiang.zhao@vip.sina.com.
PMID: 30153964 DOI: 10.1016/j.bmcl.2018.08.021
Abstract

PIN1 (Protein interaction with never in mitosis A1) is a validated molecular target for Anticancer drug discovery. Herein, we reported the design, synthesis, and structure-activity relationship study of novel ring A modified AKBA (3-acetyl-11-keto-boswellic acid) derivatives as PIN1 inhibitors. Most compounds showed superior PIN1 inhibitory activities to AKBA. One of the most promising compounds, 10a, potently inhibited PIN1 with IC50 value of 0.46 μM, while it displayed excellent anti-proliferative effect against prostate Cancer cells PC-3 with GI50 value of 1.82 μM. Structure-activity relationship indicated that reasonable structural modifications in ring A had significant impact on improving activity. Further mechanism research revealed that 10a decreased the level of Cyclin D1 and caused cell cycle arrest at G0/G1 phase in PC-3 Cancer cells. Thus, compound 10a may serve as potential anti-prostate Cancer agent for further investigation through PIN1 inhibition.

Keywords

11-Keto-boswellic acid; Anticancer; Cell cycle arrest; Pin1 inhibitors.

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