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Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models

Jie Lin1, Deepak Sampath, Michelle A Nannini

  • 1Genentech, South San Francisco, CA 94080, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|January 5, 2013
PubMed
Abstract

Insights

GDC-0068, a novel pan-Akt inhibitor, effectively blocks cancer cell growth and enhances chemotherapy. Preclinical studies show its potential for treating cancers with activated Akt signaling.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The Akt signaling pathway is frequently dysregulated in human cancers, making it a key target for therapeutic intervention.
  • Developing selective inhibitors of Akt kinase is crucial for effective cancer treatment.

Purpose of the Study:

  • To characterize the preclinical pharmacology and antitumor activity of GDC-0068, a novel ATP-competitive pan-Akt inhibitor.
  • To evaluate GDC-0068's potential in treating human cancers, particularly those with activated Akt signaling.

Main Methods:

  • Assessed GDC-0068's effect on Akt signaling using pathway-specific biomarkers.
  • Evaluated response in human cancer cell lines and xenograft models, both as a single agent and in combination therapy.
  • Investigated genetic factors influencing sensitivity to GDC-0068.

Main Results:

  • GDC-0068 demonstrated dose-dependent inhibition of Akt signaling, reducing phosphorylation of downstream targets.
  • Inhibition led to cell-cycle arrest and decreased cancer cell viability.
  • Sensitivity to GDC-0068 correlated with markers of Akt activation, including PTEN loss and PIK3CA mutations.
  • Oral administration showed significant antitumor activity in xenograft models, including tumor growth delay and regression.
  • GDC-0068 enhanced the efficacy of conventional chemotherapeutic agents.

Conclusions:

  • GDC-0068 is a potent, orally bioavailable Akt kinase inhibitor with demonstrated pharmacodynamic and antitumor effects.
  • Preclinical data support the evaluation of GDC-0068 in clinical trials for cancers with activated Akt signaling.

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