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
† State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China
‡ Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China
§ Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin 300071, China
J. Med. Chem., Article ASAP
DOI: 10.1021/acs.jmedchem.6b00943
Publication Date (Web): October 14, 2016
Copyright © 2016 American Chemical Society
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.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b00943.
- Chemical data of key intermediates, acute toxicity evaluation of compound 1 and 13an, mappings of 13b and 13ai with the pharmacophore hypothesis of hERG blockers, and kinase profiling results of 13an (PDF)
- SMILES data (CSV)
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