title: ATP-competitive inhibitors of the mammalian target of rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidines.
abstract: The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.
authors: Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. zaska@wyeth.com
authors: Arie
authors: A
authors: Zask
authors: Jeroen C
authors: JC
authors: Verheijen
authors: Kevin
authors: K
authors: Curran
authors: Joshua
authors: J
authors: Kaplan
authors: David J
authors: DJ
authors: Richard
authors: Pawel
authors: P
authors: Nowak
authors: David J
authors: DJ
authors: Malwitz
authors: Natasja
authors: N
authors: Brooijmans
authors: Joel
authors: J
authors: Bard
authors: Kristine
authors: K
authors: Svenson
authors: Judy
authors: J
authors: Lucas
authors: Lourdes
authors: L
authors: Toral-Barza
authors: Wei-Guo
authors: WG
authors: Zhang
authors: Irwin
authors: I
authors: Hollander
authors: James J
authors: JJ
authors: Gibbons
authors: Robert T
authors: RT
authors: Abraham
authors: Semiramis
authors: S
authors: Ayral-Kaloustian
authors: Tarek S
authors: TS
authors: Mansour
authors: Ker
authors: K
authors: Yu
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D058544:Class Ib Phosphatidylinositol 3-Kinase; D018360:Crystallography, X-Ray; D015195:Drug Design; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007527:Isoenzymes / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D002219:Carbamates; D058544:Class Ib Phosphatidylinositol 3-Kinase; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D014508:Urea; C546843:mTOR protein, mouse; C546764:Pik3cg protein, mouse