Pyranonaphthoquinone lactones: a new class of AKT selective kinase inhibitors alkylate a regulatory loop cysteine.
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.
Salaski
Edward J
EJ
Departments of Chemical & Screening Sciences and Oncology, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA. salaske@wyeth.com
Krishnamurthy
Girija
G
Ding
Wei-Dong
WD
Yu
Ker
K
Insaf
Shabana S
SS
Eid
Clark
C
Shim
Jaechul
J
Levin
Jeremy I
JI
Tabei
Keiko
K
Toral-Barza
Lourdes
L
Zhang
Wei-Guo
WG
McDonald
Leonard A
LA
Honores
Erick
E
Hanna
Cilien
C
Yamashita
Ayako
A
Johnson
Bernard
B
Li
Zhong
Z
Laakso
Leif
L
Powell
Dennis
D
Mansour
Tarek S
TS
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
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