Antifolate activators of AMP-dependent protein kinase

总结 大多数人类癌症已经失去了肿瘤抑制基因（LKB 1， PTEN，TSC 1/2）控制Akt-mTOR途径上的能量代谢，或者具有 癌基因（PI 3激酶，Akt）在该相同途径上的过度活性。我们发现 抑制第二叶酸依赖性酶从头嘌呤的药物 生物合成途径引起该反应的底物ZMP的积累， 并且这种内源性合成的ZMP激活AMP依赖性蛋白激酶。 激活AMP激酶的化合物具有作为抗肿瘤剂的潜力，因为这一点是可能的。 酶作为TORC 1在该途径上的关键调节剂，恢复对肿瘤的控制， 有这些基因变化的细胞。本项目拟研究嘌呤类抑制剂 在生物化学和分子遗传水平上进行合成，以确定其机制 这些效果和这些抑制剂的效用，特别是治疗癌症， PI 3激酶-mTOR通路中的遗传缺陷。的酶学和细胞生物学 先导化合物将被研究，更有效的AICART抑制剂将被研究， 甲酰转移酶反应将被设计为靶向治疗剂

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