title: Preclinical evaluation of WYE-687, a mTOR kinase inhibitor, as a potential anti-acute myeloid leukemia agent.
abstract: Mammalian target of rapamycin (mTOR) as a potential drug target for treatment of acute myeloid leukemia (AML). Here, we investigated the potential anti-leukemic activity by WYE-687, a potent mTOR kinase inhibitor. We demonstrated that WYE-687 potently inhibited survival and proliferation of established (HL-60, U937, AML-193 and THP-1 lines) and human AML progenitor cells. Yet, same WYE-687 treatment was non-cytotoxic to the primary peripheral blood mononuclear leukocytes (PBMCs) isolated from healthy donors. WYE-687 induced caspase-dependent apoptotic death in above AML cells/progenitor cells. On the other hand, the pan-caspase inhibitor (Z-VAD-FMK), the caspase-3 specific inhibitor (Z-DEVD-FMK) or the caspase-9 specific inhibitor (z-LEHD-fmk) attenuated WYE-687-induced cytotoxicity. At the molecular level, WYE-687 concurrently inhibited activation of mTORC1 (p70S6K1 and S6 phosphorylations) and mTORC2 (AKT Ser-473 and FoxO1/3a phosphorylations), whiling downregulating mTORC1/2-regulated genes (Bcl-xL and hypoxia-inducible factor 1/2α) in both HL-60/U937 cells and human AML progenitor cells. In vivo, oral administration of WYE-687 potently inhibited U937 leukemic xenograft tumor growth in severe combined immunodeficient (SCID) mice, without causing significant toxicities. In summary, our results demonstrate that targeting mTORC1/2 by WYE-687 leads to potent antitumor activity in preclinical models of AML.
authors.affiliation: Department of Hematology, Affiliated Wuxi People's Hospital, Nanjing Medical University, Wuxi 214023, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Department of Hematology, Affiliated Wuxi People's Hospital, Nanjing Medical University, Wuxi 214023, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Hematology, Affiliated Wuxi People's Hospital, Nanjing Medical University, Wuxi 214023, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Hematology, Affiliated Wuxi People's Hospital, Nanjing Medical University, Wuxi 214023, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Hematology, Affiliated Wuxi People's Hospital, Nanjing Medical University, Wuxi 214023, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Hematology, Affiliated Wuxi People's Hospital, Nanjing Medical University, Wuxi 214023, China. Electronic address: jiangyuanqiangwuxi@163.com.
authors.forename: Yuanqiang
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Hematology, Affiliated Wuxi People's Hospital, Nanjing Medical University, Wuxi 214023, China. Electronic address: lumizewuxi9@sina.com.
authors.forename: Mize
authors.initials: M
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; C000608239:WYE-687; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Acute myeloid leukemia; Apoptosis; WYE-687; mTOR