Antifolate activators of AMP-dependent protein kinase

描述（由申请人提供）：大多数人类癌症已经丧失了控制Akt-mTOR途径上能量代谢的肿瘤抑制基因（LKB 1、PTEN、TSC 1/2）的功能，或者在该相同途径上具有癌基因（PI 3激酶、Akt）的过度活性。我们已经发现，抑制嘌呤生物合成途径上的第二种叶酸依赖性酶的药物会导致该反应的底物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，因为这种酶在该途径上充当TORC 1的关键调节剂，通过这些遗传变化恢复对肿瘤细胞的控制。本项目拟在生物化学和分子遗传学水平上研究嘌呤合成抑制剂，以确定这些作用的机制以及这些抑制剂专门用于治疗PI 3激酶-mTOR通路中存在遗传缺陷的癌症的效用。先导化合物的酶学和细胞生物学将被研究，并且更有效的AICART甲酰转移酶反应抑制剂将被设计为靶向治疗剂 公共卫生相关性：大多数人类癌症已经失去了控制Akt-mTOR途径上能量代谢的肿瘤抑制基因的功能，或者在该途径上具有致癌基因的过度活性。我们已经发现，抑制嘌呤生物合成途径上的叶酸依赖性酶的药物引起代谢物ZMP的积累，ZMP可以重新激活调节该途径的AMP依赖性蛋白激酶，恢复对具有这些遗传变化的肿瘤细胞的控制。该项目建议在生物化学和分子遗传水平上研究这种效应，并开发这种叶酸依赖性酶的有效抑制剂。

DESCRIPTION (provided by applicant): 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 PUBLIC HEALTH RELEVANCE: The majorities of human cancers have lost the function of tumor suppressor genes controlling energy metabolism on the Akt-mTOR pathway or have hyperactivity of cancer-causing genes on this pathway. We have found that drugs that inhibit a folate- dependent enzyme on the purine biosynthesis pathway cause the accumulation of a metabolite, ZMP, that can reactivate the AMP-dependent protein kinase that regulates this pathway, restoring control in tumor cells with these genetic changes. This project proposes to study this effect at the biochemical and molecular genetic levels and to develop potent inhibitors of this folate-dependent enzyme.