Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity.
Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity.
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DOI：
10.1016/j.chembiol.2016.11.013
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发表时间：
2017-01-19
影响因子：
8.6
通讯作者：
Lai L
中科院分区：
文献类型：
--
作者：
Wang Q;Liberti MV;Liu P;Deng X;Liu Y;Locasale JW;Lai L
癌细胞中的代谢重编程促进生长和增殖。通过磷酸甘油酸脱氢酶（PHGDH）的丝氨酸生物合成途径的活性增加有助于肿瘤发生。由于底物小且结合辅因子（NAD+）弱，PHGDH的抑制剂开发仍然具有挑战性。而不是针对PHGDH活性位点，我们计算确定了两个潜在的变构位点和虚拟筛选的化合物，可以结合到这些网站。通过随后的表征，我们成功地鉴定了PHDGH非NAD+竞争性变构抑制剂，其减弱其酶活性，选择性抑制癌细胞中的丝氨酸从头合成，并减少体内肿瘤生长。我们的研究不仅鉴定了PHGDH的新型变构抑制剂以探测其作为治疗靶点的功能和潜力，而且还为代谢酶功能的小分子调节剂的合理设计提供了一般策略。Wang等人鉴定了PHGDH上的变构位点并发现了与这些位点结合的抑制剂。这些变构抑制剂是特异性的，与细胞中的PHGDH结合，减少丝氨酸合成，并在体内显示活性。
Metabolic reprogramming in cancer cells facilitates growth and proliferation. Increased activity of the serine biosynthetic pathway through the enzyme phosphoglycerate dehydrogenase (PHGDH) contributes to tumorigenesis. With a small substrate and a weak binding cofactor (NAD+), inhibitor development for PHGDH remains challenging. Instead of targeting the PHGDH active site, we computationally identified two potential allosteric sites and virtually screened compounds that can bind to these sites. With subsequent characterization, we successfully identified PHDGH non-NAD+ competing allosteric inhibitors that attenuate its enzyme activity, selectively inhibit de novo serine synthesis in cancer cells, and reduce tumor growth in vivo. Our study not only identifies novel allosteric inhibitors for PHGDH to probe its function and potential as a therapeutic target, but also provides a general strategy for the rational design of small molecule modulators of metabolic enzyme function. Wang et al. identify allosteric sites on PHGDH and discover inhibitors bound to these sites. These allosteric inhibitors are specific, bind to PHGDH in cells, reduce serine synthesis, and show activities in vivo.
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影响因子：
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影响因子：
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作者：
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DOI：
10.1126/science.1232033
发表时间：
2013-02-15
期刊：
Science (New York, N.Y.)
影响因子：
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影响因子：
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