Inhibition of tumor cell growth, proliferation and migration by X-387, a novel active-site inhibitor of mTOR.
The mammalian target of rapamycin (mTOR), is deregulated in about 50% of human malignancies and exists in two complexes: mTORC1 and mTORC2. Rapalogs partially inhibit mTORC1 through allosteric binding to mTORC1 and their efficacy is modest as a cancer therapy. A few mTOR kinase inhibitors that inhibit both mTORC1 and mTORC2 have been reported to possess potent anticancer activities. Herein, we designed and synthesized a series of pyrazolopyrimidine derivatives targeting mTOR kinase domain and X-387 was identified as a promising lead. X-387 selectively inhibited mTOR in an ATP-competitive manner while sparing a panel of kinases from the PIKK family. X-387 blocked mTORC1 and mTORC2-mediacted signaling pathway in cell lines with activated mTOR signaling and in rapamycin-resistant cells. Specifically, X-387 inhibited phosphorylation of AKT at T308, which is thought to be a target of PDK1 but not mTOR. Such activity was not due to inhibition of PI3K since X-387 did not inhibit translocation of AKT to the cell membrane. X-387 induced autophagy as observed for other mTOR inhibitors, while induced autophagy is pro-survival since concurrent inhibition of autophagy by 3-MA reinforced the antiproliferative activity of mTOR inhibitors. X-387 also inhibited cell motility, which is associated with decrease in activity of small GTPases such as RhoA, Rac1 and Cdc42. Taken together, X-387 is a promising compound lead targeting mTOR and with a wide spectrum anticancer activity among tumor cell lines. The data also underscores the complexity of the mTOR signaling pathways which are far from being understood.
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, PR China.
Si-meng
SM
Chen
Jia-li
JL
Liu
Xiang
X
Wang
Chris
C
Liang
Jian
J
Ding
Ling-hua
LH
Meng
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D001667:Binding, Competitive; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D051058:Oncogene Protein v-akt; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; C107953:RAC1 protein, human; C572198:X-387; C546842:MTOR protein, human