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GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K

Jeffrey J Wallin1, Kyle A Edgar, Jane Guan

  • 1Department of Translational Oncology, Genentech, Inc., South San Francisco, California 94080, USA.

Molecular Cancer Therapeutics
|October 15, 2011
PubMed

Insights

GDC-0980, a dual phosphoinositide-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor, effectively suppressed cancer cell growth and tumor progression in preclinical models. This potent compound shows promise as a novel cancer therapeutic targeting key signaling pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The phosphoinositide-3 kinase (PI3K)/Akt signaling pathway is frequently dysregulated in cancer through various mechanisms, including PIK3CA mutations and PTEN loss.
  • This pathway's involvement in tumor initiation, growth, survival, invasion, and angiogenesis makes PI3K and mTOR critical therapeutic targets.

Purpose of the Study:

  • To evaluate GDC-0980, a novel dual inhibitor of Class I PI3K and mTOR (TORC1/2), as a potential cancer therapeutic.
  • To assess its pharmacokinetic properties, in vitro potency, and in vivo efficacy in preclinical cancer models.

Main Methods:

  • GDC-0980 was characterized for its selectivity, potency, oral bioavailability, and pharmacokinetic/pharmacodynamic properties.
  • In vitro studies assessed its effects on cancer cell lines, including potency across different cancer types and induction of cell-cycle arrest and apoptosis.
  • In vivo studies utilized xenograft models to evaluate tumor growth inhibition and pharmacodynamic biomarker modulation.

Main Results:

  • GDC-0980 demonstrated potent inhibition of PI3K and mTOR signaling, leading to G1 cell-cycle arrest and apoptosis in sensitive cancer cell lines.
  • The compound showed broad potency against various cancer cell lines, with notable activity in breast, prostate, and lung cancers.
  • GDC-0980 effectively inhibited tumor growth in preclinical xenograft models, including those with PI3K pathway activation or PTEN loss.

Conclusions:

  • GDC-0980 is a potent, orally bioavailable dual PI3K/mTOR inhibitor with promising preclinical efficacy.
  • Its ability to inhibit key nodes in the PI3K/Akt/mTOR pathway suggests significant therapeutic potential for various cancers.

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