title: Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2.
abstract: The mammalian target of rapamycin (mTOR) is a major component of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway that is dysregulated in 50% of all human malignancies. Rapamycin and its analogues (rapalogs) partially inhibit mTOR through allosteric binding to mTOR complex 1 (mTORC1) but not mTOR complex 2 (mTORC2), an emerging player in cancer. Here, we report WYE-125132 (WYE-132), a highly potent, ATP-competitive, and specific mTOR kinase inhibitor (IC(50): 0.19 +/- 0.07 nmol/L; >5,000-fold selective versus PI3Ks). WYE-132 inhibited mTORC1 and mTORC2 in diverse cancer models in vitro and in vivo. Importantly, consistent with genetic ablation of mTORC2, WYE-132 targeted P-AKT(S473) and AKT function without significantly reducing the steady-state level of the PI3K/PDK1 activity biomarker P-AKT(T308), highlighting a prominent and direct regulation of AKT by mTORC2 in cancer cells. Compared with the rapalog temsirolimus/CCI-779, WYE-132 elicited a substantially stronger inhibition of cancer cell growth and survival, protein synthesis, cell size, bioenergetic metabolism, and adaptation to hypoxia. Oral administration of WYE-132 to tumor-bearing mice showed potent single-agent antitumor activity against MDA361 breast, U87MG glioma, A549 and H1975 lung, as well as A498 and 786-O renal tumors. An optimal dose of WYE-132 achieved a substantial regression of MDA361 and A549 large tumors and caused complete regression of A498 large tumors when coadministered with bevacizumab. Our results further validate mTOR as a critical driver for tumor growth, establish WYE-132 as a potent and profound anticancer agent, and provide a strong rationale for clinical development of specific mTOR kinase inhibitors as new cancer therapy.
authors.affiliation: Discovery Oncology and Discovery Medicinal Chemistry, Wyeth Research, Pearl River, New York 10965, USA. yuk@wyeth.com
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
authors.forename: Celine
authors.initials: C
authors.lastname: Shi
authors.forename: Lourdes
authors.initials: L
authors.lastname: Toral-Barza
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Boris
authors.initials: B
authors.lastname: Shor
authors.forename: Jae Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhang
authors.forename: Robert
authors.initials: R
authors.lastname: Mahoney
authors.forename: Christine
authors.initials: C
authors.lastname: Gaydos
authors.forename: Luanna
authors.initials: L
authors.lastname: Tardio
authors.forename: Sung Kyoo
authors.initials: SK
authors.lastname: Kim
authors.forename: Roger
authors.initials: R
authors.lastname: Conant
authors.forename: Kevin
authors.initials: K
authors.lastname: Curran
authors.forename: Joshua
authors.initials: J
authors.lastname: Kaplan
authors.forename: Jeroen
authors.initials: J
authors.lastname: Verheijen
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
authors.forename: Robert T
authors.initials: RT
authors.lastname: Abraham
authors.forename: Arie
authors.initials: A
authors.lastname: Zask
authors.forename: James J
authors.initials: JJ
authors.lastname: Gibbons
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C493245:CRTC2 protein, human; C547581:WYE 125132; C401859:temsirolimus; C546842:MTOR protein, human; C546843:mTOR protein, mouse