An allosteric Akt inhibitor effectively blocks Akt signaling and tumor growth with only transient effects on glucose and insulin levels in vivo Journal Article


Authors: Cherrin, C.; Haskell, K.; Howell, B.; Jones, R.; Leander, K.; Robinson, R.; Watkins, A.; Bilodeau, M.; Hoffman, J.; Sanderson, P.; Hartman, G.; Mahan, E.; Prueksaritanont, T.; Jiang, G.; She, Q. B.; Rosen, N.; Sepp-Lorenzino, L.; DeFeo-Jones, D.; Huber, H. E.
Article Title: An allosteric Akt inhibitor effectively blocks Akt signaling and tumor growth with only transient effects on glucose and insulin levels in vivo
Abstract: The PI3K-Akt pathway is dysregulated in the majority of solid tumors. Pharmacological inhibition of Akt is a promising strategy for treating tumors resistant to growth factor receptor antagonists due to mutations in PI3K or PTEN. We have developed allosteric, isozyme-specific inhibitors of Akt activity and activation, as well as ex vivo kinase assays to measure inhibition of individual Akt isozymes in tissues. Here we describe the relationship between PK, Akt inhibition, hyperglycemia and tumor efficacy for a selective inhibitor of Akt1 and Akt2 (AKTi). In nude mice, AKTi treatment caused transient insulin resistance and reversible, dose-dependent hyperglycemia and hyperinsulinemia. Akt1 and Akt2 phosphorylation was inhibited in mouse lung with EC50 values of 1.6 and 7 μM, respectively, and with similar potency in other tissues and xenograft tumors. Weekly subcutaneous dosing of AKTi resulted in dose-dependent inhibition of LNCap prostate cancer xenografts, an AR-dependent tumor with PTEN deletion and constitutively activated Akt. Complete tumor growth inhibition was achieved at 200 mpk, a dose that maintained inhibition of Akt1 and Akt2 of greater than 80 and 50%, respectively, for at least 12 h in xenograft tumor and mouse lung. Hyperglycemia could be controlled by reducing Cmax, while maintaining effi cacy in the LNCap model, but not by insulin administration. AKTi treatment was well tolerated, without weight loss or gross toxicities. These studies supported the rationale for clinical development of allosteric Akt inhibitors and provide the basis for further refining of pharmacokinetic properties and dosing regimens of this class of inhibitors. © 2010 Landes Bioscience.
Keywords: signal transduction; protein kinase b; controlled study; human cell; drug tolerability; nonhuman; animal cell; mouse; animals; mice; pharmacodynamics; animal experiment; animal model; drug potency; tumor xenograft; xenograft model antitumor assays; inhibitor; phosphorylation; mice, inbred balb c; hyperglycemia; prostate cancer; prostatic neoplasms; cancer inhibition; enzyme phosphorylation; tissue distribution; mice, nude; protein transport; proto-oncogene proteins c-akt; pten phosphohydrolase; insulin; glucose blood level; glucose; insulin blood level; insulin resistance; tumor growth; akt; indoles; isoenzymes; cell strain lncap; allosteric regulation; protein kinase b inhibitor; isozyme-specific; hyperinsulinemia; indazoles; naphthyridines
Journal Title: Cancer Biology and Therapy
Volume: 9
Issue: 7
ISSN: 1538-4047
Publisher: Taylor & Francis Group  
Date Published: 2010-04-01
Start Page: 493
End Page: 503
Language: English
PUBMED: 20139722
PROVIDER: scopus
PMCID: PMC2987445
DOI/URL:
Notes: --- - "Cited By (since 1996): 3" - "Export Date: 20 April 2011" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Neal Rosen
    426 Rosen
  2. Qing-Bai She
    31 She