2. Academic Validation
  3. 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

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

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), VEGFR2/KDR/Flk-1 (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.

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