Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2(+) Breast Cancer.
Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2(+) Breast Cancer.
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DOI：
10.1016/j.chembiol.2016.04.011
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发表时间：
2016-06-23
影响因子：
8.6
通讯作者：
Haystead TA
中科院分区：
文献类型：
--
作者：
Alwarawrah Y;Hughes P;Loiselle D;Carlson DA;Darr DB;Jordan JL;Xiong J;Hunter LM;Dubois LG;Thompson JW;Kulkarni MM;Ratcliff AN;Kwiek JJ;Haystead TA
许多肿瘤依赖于从头脂肪酸合成来维持细胞生长。脂肪酸合成酶（Fatty acid synthase，FATS-R）催化该途径的最后合成步骤，并且其上调与肿瘤侵袭性相关。急性或慢性抑制必需酶（如Festival）的后果和适应性反应尚未完全了解。在本文中，我们鉴定了Fasnall，一种通过其辅因子结合位点选择性地靶向FcB的噻吩并嘧啶。Fasnall的全球脂质组学研究显示，细胞脂质谱发生了深刻变化，神经酰胺、二酰基甘油和不饱和脂肪酸急剧增加，外源性棕榈酸酯摄取增加，更多地偏离中性脂质形成而不是磷脂。我们还表明，神经酰胺水平的增加在一定程度上有助于介导细胞凋亡。与这种作用机制一致，Fasnall在HER 2+乳腺癌的MMTV-Neu模型中显示出强效抗肿瘤活性，特别是与卡铂联合使用时。许多肿瘤依赖于从头脂肪酸合成。使用化学蛋白质组学筛选，Alwarawrah等人鉴定了Fasnall，一种噻吩并嘧啶脂肪酸合成酶抑制剂，在体外和体内显示出抗乳腺癌的抗肿瘤活性。
Many tumors are dependent on de novo fatty acid synthesis to maintain cell growth. Fatty acid synthase (FASN) catalyzes the final synthetic step of this pathway, and its upregulation is correlated with tumor aggressiveness. The consequences and adaptive responses of acute or chronic inhibition of essential enzymes such as FASN are not fully understood. Herein we identify Fasnall, a thiophenopyrimidine selectively targeting FASN through its co-factor binding sites. Global lipidomics studies with Fasnall showed profound changes in cellular lipid profiles, sharply increasing ceramides, diacylglycerols, and unsaturated fatty acids as well as increasing exogenous palmitate uptake that is deviated more into neutral lipid formation rather than phospholipids. We also showed that the increase in ceramide levels contributes to some extent in the mediation of apoptosis. Consistent with this mechanism of action, Fasnall showed potent anti-tumor activity in the MMTV-Neu model of HER2+ breast cancer, particularly when combined with carboplatin. Many tumors are dependent on de novo fatty acid synthesis. Using a chemoproteomic screen, Alwarawrah et al. identified Fasnall, a thiophenopyrimidine fatty acid synthase inhibitor that displays anti-neoplastic activity against breast cancer in vitro and in vivo.
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影响因子：
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作者：
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通讯作者：
Haystead, Timothy A. J.