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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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-10-26 00:00:00 , 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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-10-26 00:00:00 , 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
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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.
中文翻译:
从铅到药物候选者:3-(苯基乙炔基)-1 H-吡唑并[3,4- d ]嘧啶-4-胺衍生物作为治疗三阴性乳腺癌的药物的优化
本文中,我们报告了针对先前公开的Src抑制剂化合物1进行结构优化的复杂过程,该化合物在体外和体内均显示出对三阴性乳腺癌(TNBC)的高治疗能力,但具有相当大的毒性。合成了一系列的3-(苯基乙炔基)-1 H-吡唑并[3,4- d ]嘧啶-4-胺衍生物。最终基于体外细胞的表型筛选,以及体内测定和结构-活性关系(SAR)研究最终导致了N-(3-((4-氨基-1-(反式-4-羟基环己基)-1 H)的发现-吡唑并[3,4- d ]嘧啶-3-基)乙炔基)-4-甲基苯基)-4-甲基-3-(三氟甲基)苯甲酰胺(13an)。13an是一种多激酶抑制剂,可有效抑制Src(IC 50 = 0.003μM),KDR(IC 50 = 0.032μM)和几种参与MAPK信号转导的激酶。该化合物在体外和体内均显示出有效的抗TNBC活性,并具有良好的药代动力学特性和低毒性。还研究了抗TNBC的作用机理。总体而言,本研究获得的数据表明13an可能是有希望的TNBC治疗药物,因此值得进一步研究。
更新日期:2016-10-26
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
从铅到药物候选者:3-(苯基乙炔基)-1 H-吡唑并[3,4- d ]嘧啶-4-胺衍生物作为治疗三阴性乳腺癌的药物的优化
本文中,我们报告了针对先前公开的Src抑制剂化合物1进行结构优化的复杂过程,该化合物在体外和体内均显示出对三阴性乳腺癌(TNBC)的高治疗能力,但具有相当大的毒性。合成了一系列的3-(苯基乙炔基)-1 H-吡唑并[3,4- d ]嘧啶-4-胺衍生物。最终基于体外细胞的表型筛选,以及体内测定和结构-活性关系(SAR)研究最终导致了N-(3-((4-氨基-1-(反式-4-羟基环己基)-1 H)的发现-吡唑并[3,4- d ]嘧啶-3-基)乙炔基)-4-甲基苯基)-4-甲基-3-(三氟甲基)苯甲酰胺(13an)。13an是一种多激酶抑制剂,可有效抑制Src(IC 50 = 0.003μM),KDR(IC 50 = 0.032μM)和几种参与MAPK信号转导的激酶。该化合物在体外和体内均显示出有效的抗TNBC活性,并具有良好的药代动力学特性和低毒性。还研究了抗TNBC的作用机理。总体而言,本研究获得的数据表明13an可能是有希望的TNBC治疗药物,因此值得进一步研究。