title: Pyranonaphthoquinone lactones: a new class of AKT selective kinase inhibitors alkylate a regulatory loop cysteine.
abstract: The naturally occurring pyranonaphthoquinone (PNQ) antibiotic lactoquinomycin and related aglycones were found to be selective inhibitors of the serine-threonine kinase AKT. A set of synthetic PNQs were prepared and a minimum active feature set and preliminary SAR were determined. PNQ lactones inhibit the proliferation of human tumor cell lines containing constitutively activated AKT and show expected effects on cellular biomarkers. Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action.
authors.affiliation: Departments of Chemical & Screening Sciences and Oncology, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA. salaske@wyeth.com
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Salaski
authors.forename: Girija
authors.initials: G
authors.lastname: Krishnamurthy
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Ding
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
authors.forename: Shabana S
authors.initials: SS
authors.lastname: Insaf
authors.forename: Clark
authors.initials: C
authors.lastname: Eid
authors.forename: Jaechul
authors.initials: J
authors.lastname: Shim
authors.forename: Jeremy I
authors.initials: JI
authors.lastname: Levin
authors.forename: Keiko
authors.initials: K
authors.lastname: Tabei
authors.forename: Lourdes
authors.initials: L
authors.lastname: Toral-Barza
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhang
authors.forename: Leonard A
authors.initials: LA
authors.lastname: McDonald
authors.forename: Erick
authors.initials: E
authors.lastname: Honores
authors.forename: Cilien
authors.initials: C
authors.lastname: Hanna
authors.forename: Ayako
authors.initials: A
authors.lastname: Yamashita
authors.forename: Bernard
authors.initials: B
authors.lastname: Johnson
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.forename: Leif
authors.initials: L
authors.lastname: Laakso
authors.forename: Dennis
authors.initials: D
authors.lastname: Powell
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
mesh_terms: D000478:Alkylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003545:Cysteine / Q000378:metabolism*; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors*; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000095622:Benzoisochromanequinones
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D003545:Cysteine; D007783:Lactones; D009285:Naphthoquinones; D051058:Oncogene Protein v-akt; D011714:Pyrans; C018066:frenolicin B; D000095622:Benzoisochromanequinones; C013104:medermycin; C013079:kalafungin