Antifolate activators of AMP-dependent protein kinase

描述（由申请人提供）：大多数人类癌症已经失去了控制Akt- mtor通路上能量代谢的肿瘤抑制基因（LKB1， PTEN, TSC1/2）的功能，或者在同一通路上具有高活性的癌基因（PI3kinase, Akt）。我们发现，抑制新生嘌呤生物合成途径中第二种叶酸依赖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会激活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，因为该酶在该途径上作为TORC1的关键调节剂，通过这些遗传变化恢复对肿瘤细胞的控制。本项目拟从生化和分子遗传水平研究嘌呤合成抑制剂，以确定这些作用的机制，以及这些抑制剂特异性地用于治疗PI3kinase-mTOR通路中存在遗传缺陷的癌症。研究先导化合物的酶学和细胞生物学，设计更有效的AICART甲酰转移酶反应抑制剂作为靶向治疗剂

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.