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Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349

Zhonghua Pei1, Elizabeth Blackwood1, Lichuan Liu1

  • 1Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.

ACS Medicinal Chemistry Letters
|June 6, 2014
PubMed

Insights

Aberrant activation of the PI3K-Akt-mTOR pathway is common in cancers. Researchers developed GDC-0349, a potent mTOR inhibitor, showing efficacy in preclinical cancer models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Aberrant activation of the PI3K-Akt-mTOR signaling pathway is implicated in human cancers.
  • This pathway represents a potential therapeutic target for cancer treatment.

Purpose of the Study:

  • To discover and develop novel inhibitors targeting the mTOR pathway.
  • To evaluate the preclinical efficacy of a newly developed mTOR inhibitor, GDC-0349.

Main Methods:

  • Lead optimization of advanced compound 1.
  • Characterization of GDC-0349 as a potent and selective ATP-competitive mTOR inhibitor.
  • Assessment of pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.

Main Results:

  • Discovery of GDC-0349 (compound 8h) as a clinical development candidate.
  • GDC-0349 demonstrated potent and selective inhibition of mTOR.
  • GDC-0349 showed significant pathway modulation and dose-dependent efficacy in preclinical cancer models.

Conclusions:

  • GDC-0349 is a promising therapeutic candidate targeting the PI3K-Akt-mTOR pathway in cancer.
  • Further clinical investigation of GDC-0349 for cancer treatment is warranted.
Keywords:
Mammalian target of rapamycinTDImTORurea bioisostere

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