title: Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors: discovery of PKI-402.
abstract: Herein we describe the identification and lead optimization of triazolopyrimidines as a novel class of potent dual PI3K/mTOR inhibitors, resulting in the discovery of 3 (PKI-402). Compound 3 exhibits good physical properties and PK parameters, low nanomolar potency against PI3Kalpha and mTOR, and excellent inhibition of cell proliferation in several human cancer cell lines. Furthermore, in vitro and in vivo biomarker studies demonstrated the ability of 3 to shut down the PI3K/Akt pathway and induce apoptosis in cancer cells. In addition, 3 showed excellent in vivo efficacy in various human cancer xenografts, validating suppression of PI3K/mTOR signaling as a potential anticancer therapy.
authors.affiliation: Discovery Medicinal Chemistry, Wyeth Research, Pearl River, New York 10965, USA. dehnhac@wyeth.com
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Dehnhardt
authors.forename: Aranapakam M
authors.initials: AM
authors.lastname: Venkatesan
authors.forename: Efren
authors.initials: E
authors.lastname: Delos Santos
authors.forename: Zecheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Santos
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Natasja
authors.initials: N
authors.lastname: Brooijmans
authors.forename: Robert
authors.initials: R
authors.lastname: Mallon
authors.forename: Irwin
authors.initials: I
authors.lastname: Hollander
authors.forename: Larry
authors.initials: L
authors.lastname: Feldberg
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Inder
authors.initials: I
authors.lastname: Chaudhary
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
authors.forename: Jay
authors.initials: J
authors.lastname: Gibbons
authors.forename: Robert
authors.initials: R
authors.lastname: Abraham
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058544:Class Ib Phosphatidylinositol 3-Kinase; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D058570:TOR Serine-Threonine Kinases; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D014230:Triazoles; C546842:MTOR protein, human; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases