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Cellular Pharmacodynamics of a Novel Pyrrolo[3,2-d]pyrimidine Inhibitor Targeting Mitochondrial and Cytosolic One-Carbon Metabolism.
Molecular Pharmacology ( IF 3.2 ) Pub Date : 2019-11-09 , DOI: 10.1124/mol.119.117937 Aamod S Dekhne 1 , Changwen Ning 1 , Md Junayed Nayeen 1 , Khushbu Shah 1 , Hasini Kalpage 1 , Josephine Frühauf 1 , Adrianne Wallace-Povirk 1 , Carrie O'Connor 1 , Zhanjun Hou 1 , Seongho Kim 1 , Maik Hüttemann 1 , Aleem Gangjee 2 , Larry H Matherly 2
Molecular Pharmacology ( IF 3.2 ) Pub Date : 2019-11-09 , DOI: 10.1124/mol.119.117937 Aamod S Dekhne 1 , Changwen Ning 1 , Md Junayed Nayeen 1 , Khushbu Shah 1 , Hasini Kalpage 1 , Josephine Frühauf 1 , Adrianne Wallace-Povirk 1 , Carrie O'Connor 1 , Zhanjun Hou 1 , Seongho Kim 1 , Maik Hüttemann 1 , Aleem Gangjee 2 , Larry H Matherly 2
Affiliation
Folate-dependent one-carbon (C1) metabolism is compartmentalized in the mitochondria and cytosol and is a source of critical metabolites for proliferating tumors. Mitochondrial C1 metabolism including serine hydroxymethyltransferase 2 (SHMT2) generates glycine for de novo purine nucleotide and glutathione biosynthesis and is an important source of NADPH, ATP, and formate, which affords C1 units as 10-formyl-tetrahydrofolate and 5,10-methylene-tetrahydrofolate for nucleotide biosynthesis in the cytosol. We previously discovered novel first-in-class multitargeted pyrrolo[3,2-d]pyrimidine inhibitors of SHMT2 and de novo purine biosynthesis at glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase with potent in vitro and in vivo antitumor efficacy toward pancreatic adenocarcinoma cells. In this report, we extend our findings to an expanded panel of pancreatic cancer models. We used our lead analog AGF347 [(4-(4-(2-amino-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl)-2-fluorobenzoyl)-l-glutamic acid] to characterize pharmacodynamic determinants of antitumor efficacy for this series and demonstrated plasma membrane transport into the cytosol, uptake from cytosol into mitochondria, and metabolism to AGF347 polyglutamates in both cytosol and mitochondria. Antitumor effects of AGF347 downstream of SHMT2 and purine biosynthesis included suppression of mammalian target of rapamycin signaling, and glutathione depletion with increased levels of reactive oxygen species. Our results provide important insights into the cellular pharmacology of novel pyrrolo[3,2-d]pyrimidine inhibitors as antitumor compounds and establish AGF347 as a unique agent for potential clinical application for pancreatic cancer, as well as other malignancies. SIGNIFICANCE STATEMENT: This study establishes the antitumor efficacies of novel inhibitors of serine hydroxymethyltransferase 2 and of cytosolic targets toward a panel of clinically relevant pancreatic cancer cells and demonstrates the important roles of plasma membrane transport, mitochondrial accumulation, and metabolism to polyglutamates of the lead compound AGF347 to drug activity. We also establish that loss of serine catabolism and purine biosynthesis resulting from AGF347 treatment impacts mammalian target of rapamycin signaling, glutathione pools, and reactive oxygen species, contributing to antitumor efficacy.
中文翻译:
靶向线粒体和胞质单碳代谢的新型吡咯并[3,2-d]嘧啶抑制剂的细胞药效学。
叶酸依赖的一碳(C1)代谢在线粒体和细胞质中被分隔开,并且是肿瘤扩散的关键代谢产物的来源。线粒体C1代谢包括丝氨酸羟甲基转移酶2(SHMT2)产生了用于从头嘌呤核苷酸和谷胱甘肽生物合成的甘氨酸,并且是NADPH,ATP和甲酸盐的重要来源,其提供C1单元为10-甲酰基-四氢叶酸和5,10-亚甲基-四氢叶酸可用于胞质溶胶中的核苷酸生物合成。我们先前发现了SHMT2的新型一流多靶点吡咯并[3,2-d]嘧啶抑制剂和嘌呤酰胺在核糖酰胺核糖核苷酸甲酰基转移酶和5-氨基咪唑-4-羧酰胺核糖核苷酸甲酰基转移酶上的生物合成,具有强大的体外和体内抗肿瘤功效对胰腺腺癌细胞。在本报告中,我们将发现扩展到胰腺癌模型的扩展面板。我们使用了我们的铅类似物AGF347 [(4-(4-(2-氨基-4-氧代-3,4-二氢-5H-吡咯并[3,2-d]嘧啶-5-基)丁基)-2-氟苯甲酰基)-1-谷氨酸]来表征该系列药物抗肿瘤药效的决定因素,并证明质膜转运到细胞质中,从细胞质中吸收到线粒体中,并代谢为细胞质和线粒体中的AGF347聚谷氨酸。SHMT2下游的AGF347的抗肿瘤作用和嘌呤的生物合成包括抑制雷帕霉素信号转导的哺乳动物靶标以及随着活性氧水平的升高而减少谷胱甘肽。我们的结果为新型吡咯菌的细胞药理学提供了重要见解[3,2-d]嘧啶抑制剂可作为抗肿瘤化合物,并确立AGF347作为胰腺癌以及其他恶性肿瘤潜在临床应用的独特药物。意义声明:这项研究建立了丝氨酸羟甲基转移酶2和细胞质靶标的新型抑制剂对一组临床相关的胰腺癌细胞的抗肿瘤作用,并证明了质膜转运,线粒体积累和新陈代谢对先导化合物多聚谷氨酸的重要作用。 AGF347具有药物活性。我们还确定,AGF347治疗导致的丝氨酸分解代谢和嘌呤生物合成损失会影响雷帕霉素信号转导,谷胱甘肽库和活性氧物种的哺乳动物靶点,从而有助于抗肿瘤功效。
更新日期:2019-11-01
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
靶向线粒体和胞质单碳代谢的新型吡咯并[3,2-d]嘧啶抑制剂的细胞药效学。
叶酸依赖的一碳(C1)代谢在线粒体和细胞质中被分隔开,并且是肿瘤扩散的关键代谢产物的来源。线粒体C1代谢包括丝氨酸羟甲基转移酶2(SHMT2)产生了用于从头嘌呤核苷酸和谷胱甘肽生物合成的甘氨酸,并且是NADPH,ATP和甲酸盐的重要来源,其提供C1单元为10-甲酰基-四氢叶酸和5,10-亚甲基-四氢叶酸可用于胞质溶胶中的核苷酸生物合成。我们先前发现了SHMT2的新型一流多靶点吡咯并[3,2-d]嘧啶抑制剂和嘌呤酰胺在核糖酰胺核糖核苷酸甲酰基转移酶和5-氨基咪唑-4-羧酰胺核糖核苷酸甲酰基转移酶上的生物合成,具有强大的体外和体内抗肿瘤功效对胰腺腺癌细胞。在本报告中,我们将发现扩展到胰腺癌模型的扩展面板。我们使用了我们的铅类似物AGF347 [(4-(4-(2-氨基-4-氧代-3,4-二氢-5H-吡咯并[3,2-d]嘧啶-5-基)丁基)-2-氟苯甲酰基)-1-谷氨酸]来表征该系列药物抗肿瘤药效的决定因素,并证明质膜转运到细胞质中,从细胞质中吸收到线粒体中,并代谢为细胞质和线粒体中的AGF347聚谷氨酸。SHMT2下游的AGF347的抗肿瘤作用和嘌呤的生物合成包括抑制雷帕霉素信号转导的哺乳动物靶标以及随着活性氧水平的升高而减少谷胱甘肽。我们的结果为新型吡咯菌的细胞药理学提供了重要见解[3,2-d]嘧啶抑制剂可作为抗肿瘤化合物,并确立AGF347作为胰腺癌以及其他恶性肿瘤潜在临床应用的独特药物。意义声明:这项研究建立了丝氨酸羟甲基转移酶2和细胞质靶标的新型抑制剂对一组临床相关的胰腺癌细胞的抗肿瘤作用,并证明了质膜转运,线粒体积累和新陈代谢对先导化合物多聚谷氨酸的重要作用。 AGF347具有药物活性。我们还确定,AGF347治疗导致的丝氨酸分解代谢和嘌呤生物合成损失会影响雷帕霉素信号转导,谷胱甘肽库和活性氧物种的哺乳动物靶点,从而有助于抗肿瘤功效。