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 途径能量代谢的肿瘤抑制基因（LKB1、PTEN、TSC1/2）的功能，或者在同一途径上癌基因（PI3激酶、Akt）过度活跃。我们发现，抑制嘌呤从头生物合成途径中第二种叶酸依赖性酶的药物会导致该反应的底物 ZMP 积累，并且这种内源合成的 ZMP 会激活 AMP 依赖性蛋白激酶。激活 AMP 激酶的化合物具有作为抗肿瘤药物的潜力，因为这种酶在该通路上充当 TORC1 的关键调节因子，通过这些遗传变化恢复肿瘤细胞的控制。该项目拟在生化和分子遗传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在治疗 PI3kinase-mTOR 通路中存在遗传缺陷的癌症方面的用途。将研究先导化合物的酶学和细胞生物学，并将设计更有效的 AICART 甲酰基转移酶反应抑制剂作为靶向治疗剂 公共健康相关性：大多数人类癌症已经丧失了控制 Akt-mTOR 途径能量代谢的抑癌基因的功能，或者该途径上的致癌基因过度活跃。我们发现，抑制嘌呤生物合成途径中叶酸依赖性酶的药物会导致代谢物 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，通过这些基因变化恢复肿瘤细胞的控制。该项目拟在生化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.