Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of the oral AKT inhibitor GSK2141795 (GSK795) in a phase I first-in-human study.

Burris, Howard A.; Siu, L.L.; Infante, J. R.; Wheler, J. J.; Kurkjian, Carla; Opalinska, Joanna; Smith, Deborah A.; Antal, Joyce; Gauvin, Jennifer; González, Teresita Pérez; Adams, Laurel M.; Bédard, Philippe L.; Gerecitano, John F.; Kurzrock, Razelle; Moore, Kathleen N.; Morris, Shannon R.; Aghajanian, Carol

doi:10.1200/jco.2011.29.15_suppl.3003

Cited by 41 publications

(29 citation statements)

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“…Although some patients showed partial response and stable disease on treatment with single agent GSK2141795 in the dose escalation study [18], the overall clinical activity was modest in this unselected patient population, consistent with the results from other agents targeting PI3K-AKT pathway [8]. Mutations in KRAS or BRAF are associated with resistance to AKT inhibitors and inhibition of PI3K/AKT/mTOR signaling may lead to activation of the MEK/ERK signaling [28]–[30] which can confer resistance to PI3K pathway inhibitors [30]–[32].…”

Section: Discussionmentioning

confidence: 98%

Discovery of Novel AKT Inhibitors with Enhanced Anti-Tumor Effects in Combination with the MEK Inhibitor

et al. 2014

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Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.

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Section: Discussionmentioning

confidence: 98%

Discovery of Novel AKT Inhibitors with Enhanced Anti-Tumor Effects in Combination with the MEK Inhibitor

et al. 2014

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“…This is in contrast to previous reports with other pan-AKT inhibitors in which hyperglycemia was seen in approximately 15% to 20% of patients. 25,26 Of note, serial serum glucose sampling and plasma insulin monitoring were planned in this study only in those patients achieving serum drug concentrations corresponding to those leading to changes in insulin concentrations in preclinical animal models. Since only a few patients in our study fulfilled these criteria, correlation between plasma afuresertib concentrations and glucose or insulin levels could not be demonstrated.…”

Section: Discussionmentioning

confidence: 99%

The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma

Spencer

Yoon

Harrison

et al. 2014

Blood

116

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“…As an ATPcompetitive inhibitor, selective targeting of activated Akt is expected to further increase GDC-0068 0 s effectiveness in cells with high pAkt levels (29), such as tumor cells with PTEN-loss (31), whereas decrease its potency in cells with low Akt activity, such as normal cells, thereby potentially widen its therapeutic index. Interestingly, different safety profiles have been observed between allosteric and ATP-competitive inhibitors in the clinic, for example, rash is reported as a dose-limiting toxicity for the allosteric inhibitor MK2206 but not several ATP-competitive Akt inhibitors including GDC-0068 (36)(37)(38), raising the possibility that differences in on-target effects on normal cells could exist between the 2 classes of inhibitors due to their different mechanisms of action.…”

Section: Discussionmentioning

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

243

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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Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of the oral AKT inhibitor GSK2141795 (GSK795) in a phase I first-in-human study.

Cited by 41 publications

References 0 publications

Discovery of Novel AKT Inhibitors with Enhanced Anti-Tumor Effects in Combination with the MEK Inhibitor

Discovery of Novel AKT Inhibitors with Enhanced Anti-Tumor Effects in Combination with the MEK Inhibitor

The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma

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

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