Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells
Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells
复制标题
DOI：
10.1016/j.bmcl.2019.07.011
复制
发表时间：
2019-09-01
影响因子：
2.7
通讯作者：
Cantley, Lewis C.
中科院分区：
文献类型：
--
作者：
Mullarky, Edouard;Xu, Jiayi;Cantley, Lewis C.
癌细胞重新编程自己的新陈代谢，以支持生长和缓解细胞压力。丝氨酸合成途径被认为是一种在癌症中经常改变的代谢途径，人们对开发针对这一途径的药理药物非常感兴趣。在这里，我们报告了一系列吲哚酰胺类化合物，它们抑制人类3-磷酸甘油酸脱氢酶(PHGDH)，该酶催化丝氨酸合成途径的第一步。用X-射线结晶学研究表明，吲哚酰胺结合在PHGDH的NAD(+)口袋上。通过基于结构的优化，我们能够在酶促IC50实验中开发出对PHGDH具有低纳摩尔亲和力的化合物。在细胞检测中，最有效的化合物以低微摩尔到亚微摩尔的活性抑制丝氨酸的从头合成，并且这些化合物成功地抑制了癌细胞在无丝氨酸介质中的增殖。这里报道的吲哚酰胺系列代表着对之前发表的PHGDH抑制剂的重要改进，因为它们明显更有效，其作用机制也得到了更好的定义。
Cancer cells reprogram their metabolism to support growth and to mitigate cellular stressors. The serine synthesis pathway has been identified as a metabolic pathway frequently altered in cancers and there has been considerable interest in developing pharmacological agents to target this pathway. Here, we report a series of indole amides that inhibit human 3-phosphoglycerate dehydrogenase (PHGDH), the enzyme that catalyzes the first committed step of the serine synthesis pathway. Using X-ray crystallography, we show that the indole amides bind the NAD(+) pocket of PHGDH. Through structure-based optimization we were able to develop compounds with low nanomolar affinities for PHGDH in an enzymatic IC50 assay. In cellular assays, the most potent compounds inhibited de novo serine synthesis with low micromolar to sub-micromolar activities and these compounds successfully abrogated the proliferation of cancer cells in serine free media. The indole amide series reported here represent an important improvement over previously published PHGDH inhibitors as they are markedly more potent and their mechanism of action is better defined.