Antifolate activators of AMP-dependent protein kinase

摘要 大多数人类癌症已经失去了肿瘤抑制基因(LKB1， PTEN，TSC1/2)控制Akt-mTOR途径上的能量代谢或HAVE 癌基因(PI3K，Akt)在同一途径上的过度活跃。我们发现， 抑制从头生成嘌呤的第二叶酸依赖酶的药物 生物合成途径导致该反应的底物ZMP的积累， 这种内源性合成的ZMP激活了AMP依赖的蛋白激酶。 激活AMP激酶的化合物具有作为抗肿瘤药物的潜力，因为 酶在这一途径上扮演TORC1的关键调节者，恢复对肿瘤的控制 具有这些基因变化的细胞。这个项目计划研究嘌呤的抑制剂。 在生化和分子遗传水平上的合成以确定其作用机制 这些作用以及这些抑制剂在治疗癌症方面的作用 PI3K-mTOR通路中的遗传缺陷。黄曲霉毒素的酶学和细胞生物学 将研究先导化合物，以及更有效的AICART抑制剂 甲酰转移酶反应将被设计为靶向治疗药物

Summary The majority of human cancers have lost the function of tumor suppressor genes (LKB1, PTEN, TSC1/2) controlling energy metabolism on the Akt-mTOR pathway or have hyperactivity of oncogenes (PI3kinase, Akt) on this same pathway. We have found that drugs that inhibit the second folate-dependent enzyme on the de novo purine biosynthesis pathway cause the accumulation of the substrate for that reaction, ZMP, and that this endogenously synthesized ZMP activates AMP-dependent protein kinase. Compounds that activate AMP kinase hava potential as antitumor agents since this enzyme acts as a key regulator of TORC1 on this pathway, restoring control in tumor cells with these genetic changes. This project proposes to study inhibitors of purine synthesis at the biochemical and molecular genetic levels to determine the mechanism of these effects and the utility of these inhibitors specifically to treat cancers that have genetic defects in the PI3kinase-mTOR pathway. The enzymology and cell biology of the lead compounds would be studied, and more potent inhibitors of the AICART formyltransferase reaction would be designed as targeted therapeutic agents