Discovery and Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the Treatment of Human Tumors

Blake, James F.; Xu, Rui; Bencsik, Josef R.; Xiao, Duan; Kallan, Nicholas C.; Schlachter, Stephen T.; Mitchell, Ian S.; Spencer, Keith L.; Banka, Anna L.; Wallace, Eli M.; Gloor, Susan L.; Martinson, Matthew; Woessner, Richard; Vigers, Guy; Brandhuber, Barbara J.; Liang, Jun; Safina, Brian S.; Li, Jun; Zhang, Birong; Chabot, Christine; Do, Steven; Lee, Leslie; Oeh, Jason; Sampath, Deepak; Lee, Brian B.; Lin, Kui; Liederer, Bianca M.; Skelton, Nicholas J.

doi:10.1021/jm301024w

Cited by 164 publications

(125 citation statements)

References 29 publications

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“…S1; ref. 26) and is equipotent against all 3 Akt isoforms, which share more than 95% sequence identity within the ATP-binding pocket, with potencies ranging from 5 to 18 nmol/L (Supplementary Table S1). …”

Section: Resultsmentioning

confidence: 99%

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Targeting Activated Akt with GDC-0068, a Novel Selective Akt Inhibitor That Is Efficacious in Multiple Tumor Models

Lin

Sampath

Nannini

et al. 2013

Clinical Cancer Research

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193

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Purpose: We describe the preclinical pharmacology and antitumor activity of GDC-0068, a novel highly selective ATP-competitive pan-Akt inhibitor currently in clinical trials for the treatment of human cancers.Experimental Design: The effect of GDC-0068 on Akt signaling was characterized using specific biomarkers of the Akt pathway, and response to GDC-0068 was evaluated in human cancer cell lines and xenograft models with various genetic backgrounds, either as a single agent or in combination with chemotherapeutic agents.Results: GDC-0068 blocked Akt signaling both in cultured human cancer cell lines and in tumor xenograft models as evidenced by dose-dependent decrease in phosphorylation of downstream targets. Inhibition of Akt activity by GDC-0068 resulted in blockade of cell-cycle progression and reduced viability of cancer cell lines. Markers of Akt activation, including high-basal phospho-Akt levels, PTEN loss, and PIK3CA kinase domain mutations, correlate with sensitivity to GDC-0068. Isogenic PTEN knockout also sensitized MCF10A cells to GDC-0068. In multiple tumor xenograft models, oral administration of GDC-0068 resulted in antitumor activity ranging from tumor growth delay to regression. Consistent with the role of Akt in a survival pathway, GDC-0068 also enhanced antitumor activity of classic chemotherapeutic agents.Conclusions: GDC-0068 is a highly selective, orally bioavailable Akt kinase inhibitor that shows pharmacodynamic inhibition of Akt signaling and robust antitumor activity in human cancer cells in vitro and in vivo. Our preclinical data provide a strong mechanistic rationale to evaluate GDC-0068 in cancers with activated Akt signaling.

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Section: Resultsmentioning

confidence: 99%

“…Thus, with the exception of PKG1 (relative to which GDC-0068 is >10-fold more selective for Akt1), GDC-0068 displays a more than 100-fold selectivity for Akt1 over the next most potently inhibited non-Akt kinase, p70S6K, in the screening kinase panel (Supplementary Table S1; ref. 26).…”

Section: Resultsmentioning

confidence: 99%

Targeting Activated Akt with GDC-0068, a Novel Selective Akt Inhibitor That Is Efficacious in Multiple Tumor Models

Lin

Sampath

Nannini

et al. 2013

Clinical Cancer Research

Self Cite

250

193

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“…To confirm the specificity of the effects obtained with GSK690693, we tested other Akt inhibitors, including GDC-0068, a structurally unrelated ATP-competitive inhibitor of the Akt family (55), and MK2206, an allosteric inhibitor that binds to the pleckstrin homology domain of the Akts (56). Surprisingly, neither GDC-0068 at 2.5 M nor MK2206 at 5 M had any effect on the cytoplasmic translocation of YAP induced by ANG II in IEC-18 cells (Fig.…”

Section: Gpcr Agonists Induce Rapid Increase In the Phosphorylationmentioning

confidence: 97%

Biphasic Regulation of Yes-associated Protein (YAP) Cellular Localization, Phosphorylation, and Activity by G Protein-coupled Receptor Agonists in Intestinal Epithelial Cells

Wang¹,

Sinnett‐Smith

Stevens³

et al. 2016

Journal of Biological Chemistry

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“…GDC-0068, a potent, orally bioavailable, selective pan-Akt inhibitor, was identified by structure-guided drug design (17). The enzymatic IC 50 values of GDC-0068 range from 5 to 30 nmol/L for the three isoforms of Akt (18). Cancer cell lines with activated Akt signaling (e.g., via PTEN loss, PIK3CA mutations or ERBB2 amplification) are sensitive to Akt inhibition (19,20).…”

Section: Introductionmentioning

confidence: 99%

Evaluation and Clinical Analyses of Downstream Targets of the Akt Inhibitor GDC-0068

Yan

Serra²,

Prudkin

et al. 2013

Clinical Cancer Research

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Purpose: The oncogenic PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer. However, it is unknown whether the pathway blockade required for tumor growth inhibition is clinically achievable. Therefore, we conducted pharmacodynamic studies with GDC-0068, an ATP competitive, selective Akt1/2/3 inhibitor, in preclinical models and in patients treated with this compound. Experimental Design: We used a reverse phase protein array (RPPA) platform to identify a biomarker set indicative of Akt inhibition in cell lines and human-tumor xenografts, and correlated the degree of pathway inhibition with antitumor activity. Akt pathway activity was measured using this biomarker set in pre- and post-dose tumor biopsies from patients treated with GDC-0068 in the dose escalation clinical trial. Results: The set of biomarkers of Akt inhibition is composed of 10 phosphoproteins, including Akt and PRAS40, and is modulated in a dose-dependent fashion, both in vitro and in vivo. In human-tumor xenografts, this dose dependency significantly correlated with tumor growth inhibition. Tumor biopsies from patients treated with GDC-0068 at clinically achievable doses attained a degree of biomarker inhibition that correlated with tumor growth inhibition in preclinical models. In these clinical samples, compensatory feedback activation of ERK and HER3 was observed, consistent with preclinical observations. Conclusion: This study identified a set of biomarkers of Akt inhibition that can be used in the clinical setting to assess target engagement. Here, it was used to show that robust Akt inhibition in tumors from patients treated with GDC-0068 is achievable, supporting the clinical development of this compound in defined patient populations. Clin Cancer Res; 19(24); 6976–86. ©2013 AACR.

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Discovery and Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the Treatment of Human Tumors

Cited by 164 publications

References 29 publications

Targeting Activated Akt with GDC-0068, a Novel Selective Akt Inhibitor That Is Efficacious in Multiple Tumor Models

Targeting Activated Akt with GDC-0068, a Novel Selective Akt Inhibitor That Is Efficacious in Multiple Tumor Models

Biphasic Regulation of Yes-associated Protein (YAP) Cellular Localization, Phosphorylation, and Activity by G Protein-coupled Receptor Agonists in Intestinal Epithelial Cells

Evaluation and Clinical Analyses of Downstream Targets of the Akt Inhibitor GDC-0068

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