2. Academic Validation
  3. Design, synthesis and biological evaluation of tetrahydronaphthyridine derivatives as bioavailable CDK4/6 inhibitors for cancer therapy

Design, synthesis and biological evaluation of tetrahydronaphthyridine derivatives as bioavailable CDK4/6 inhibitors for cancer therapy

  • Eur J Med Chem. 2018 Mar 25:148:140-153. doi: 10.1016/j.ejmech.2018.02.022.
Chuantao Zha 1,  Wenjia Deng 2,  Yan Fu 1,  Shuai Tang 3,  Xiaojing Lan 3,  Yan Ye 1,  Yi Su 3,  Lei Jiang 1,  Yi Chen 3,  Ying Huang 1,  Jian Ding 3,  Meiyu Geng 3,  Min Huang 4,  Huixin Wan 5
Affiliations

Affiliations

  • 1 Shanghai HaiHe Pharmaceutical, Co. Ltd, No. 421 Newton Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, China.
  • 2 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, China.
  • 4 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, China. Electronic address: mhuang@simm.ac.cn.
  • 5 Shanghai HaiHe Pharmaceutical, Co. Ltd, No. 421 Newton Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, China. Electronic address: hxwan1978@hotmail.com.
PMID: 29459274 DOI: 10.1016/j.ejmech.2018.02.022
Abstract

CDK4/6 pathway is an attractive chemotherapeutic target for antitumor drug discovery and development. Herein, we reported the structure-based design and synthesis of a series of novel tetrahydronaphthyridine analogues as selective CDK4/6 inhibitors. Compound 5 was identified as a hit and then systematically structure optimization study was conducted. These efforts led to compound 28, which exhibited excellent in vitro potencies against CDK4/6 enzymatic activity with high selectivity over CDK1, and against Colo-205 cell growth. The compound demonstrated favorable in vitro metabolic and robust mice pharmacokinetic properties. In Colo-205 xenograft models, compound 28 showed potent tumor growth inhibition with acceptable toxic effects, which could serve as a novel Anticancer agent for further preclinical study.

Keywords

In vivo antitumor activity; Selective CDK4/6 inhibitors; Structure-activity relationship study; Structure-based drug design.

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