2. Academic Validation
  3. Pyranonaphthoquinone lactones: a new class of AKT selective kinase inhibitors alkylate a regulatory loop cysteine

Pyranonaphthoquinone lactones: a new class of AKT selective kinase inhibitors alkylate a regulatory loop cysteine

  • J Med Chem. 2009 Apr 23;52(8):2181-4. doi: 10.1021/jm900075g.
Edward J Salaski 1,  Girija Krishnamurthy,  Wei-Dong Ding,  Ker Yu,  Shabana S Insaf,  Clark Eid,  Jaechul Shim,  Jeremy I Levin,  Keiko Tabei,  Lourdes Toral-Barza,  Wei-Guo Zhang,  Leonard A McDonald,  Erick Honores,  Cilien Hanna,  Ayako Yamashita,  Bernard Johnson,  Zhong Li,  Leif Laakso,  Dennis Powell,  Tarek S Mansour
Affiliations

Affiliation

  • 1 Departments of Chemical & Screening Sciences and Oncology, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA. [email protected]
PMID: 19309081 DOI: 10.1021/jm900075g
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.

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