From Lead to Drug Candidate: Optimization of 3-(Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Derivatives as Agents for the Treatment of Triple Negative Breast Cancer

  • J Med Chem. 2016 Nov 10;59(21):9788-9805. doi: 10.1021/acs.jmedchem.6b00943.
Chun-Hui Zhang  1 ,  Kai Chen  1 ,  Yan Jiao  1 ,  Lin-Li Li  2 ,  Ya-Ping Li  1 ,  Rong-Jie Zhang  1 ,  Ming-Wu Zheng  1 ,  Lei Zhong  1 ,  Shen-Zhen Huang  1 ,  Chun-Li Song  2 ,  Wan-Ting Lin  1 ,  Jiao Yang  1 ,  Rong Xiang  3 ,  Bing Peng  1 ,  Jun-Hong Han  1 ,  Guang-Wen Lu  1 ,  Yu-Quan Wei  1 ,  Sheng-Yong Yang  1
Affiliations
  • 1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University , Sichuan 610041, China.
  • 2. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, China.
  • 3. Department of Clinical Medicine, School of Medicine, Nankai University , Tianjin 300071, China.
PMID: 27739679 DOI: 10.1021/acs.jmedchem.6b00943
Abstract

Herein we report the sophisticated process of structural optimization toward a previously disclosed Src Inhibitor, compound 1, which showed high potency in the treatment of triple negative breast Cancer (TNBC) both in vitro and in vivo but had considerable toxicity. A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were synthesized. In vitro cell-based phenotypic screening together with in vivo assays and structure-activity relationship (SAR) studies finally led to the discovery of N-(3-((4-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (13an). 13an is a multikinase inhibitor, which potently inhibited Src (IC50 = 0.003 μM), KDR (IC50 = 0.032 μM), and several kinases involved in the MAPK signal transduction. This compound showed potent anti-TNBC activities both in vitro and in vivo, and good pharmacokinetic properties and low toxicity. Mechanisms of action of anti-TNBC were also investigated. Collectively, the data obtained in this study indicate that 13an could be a promising drug candidate for the treatment of TNBC and hence merits further studies.