Allosteric inhibitors of Akt1 and Akt2: A naphthyridinone with efficacy in an A2780 tumor xenograft model

Bilodeau, Mark T.; Balitza, Adrienne E.; Hoffman, J. M.; Manley, Peter J.; Barnett, Stanley F.; Defeo-Jones, Deborah; Haskell, Kathleen; Leander, Karen; Robinson, R.; Smith, Anthony M.; Huber, Hans E.; Hartman, George D.

doi:10.1016/j.bmcl.2008.04.074

Cited by 71 publications

(57 citation statements)

References 16 publications

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“…We therefore asked whether experimental suppression of AKT signaling could actually induce G0-like cancer cells rather than killing them. We treated MCF7 cells with a smallmolecule, allosteric AKT-1/2 inhibitor (AKT-1/2i) for 72 h and looked for G0-like cells (20). As expected, low-dose AKT-1/2i (0.1 μM) had no appreciable effect on these cells, whereas a high dose (5 μM) induced significant apoptosis (Fig.…”

Section: G0-like Cancer Cells In Vitromentioning

confidence: 60%

Asymmetric cancer cell division regulated by AKT

Dey‐Guha

Wolfer

Yeh

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

128

120

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Human tumors often contain slowly proliferating cancer cells that resist treatment, but we do not know precisely how these cells arise. We show that rapidly proliferating cancer cells can divide asymmetrically to produce slowly proliferating "G0-like" progeny that are enriched following chemotherapy in breast cancer patients. Asymmetric cancer cell division results from asymmetric suppression of AKT/PKB kinase signaling in one daughter cell during telophase of mitosis. Moreover, inhibition of AKT signaling with smallmolecule drugs can induce asymmetric cancer cell division and the production of slow proliferators. Cancer cells therefore appear to continuously flux between symmetric and asymmetric division depending on the precise state of their AKT signaling network. This model may have significant implications for understanding how tumors grow, evade treatment, and recur.quiescence | epigenetics | cell signaling | drug resistance T umors generally evolve through years of mutation and clonal selection (1). This favors the outgrowth of rapidly proliferating cancer cells over time. However, even advanced tumors contain many cancer cells that appear to be proliferating slowly (2). This proliferative heterogeneity correlates closely with time to clinical detection, growth, metastasis, and treatment response across all tumor types, but we still do not understand clearly how it arises. The rate of mammalian cell proliferation is generally determined by the time spent in G1 of the cell cycle. Critical genetic and epigenetic changes within cancer cells accelerate G1 transit, whereas a suboptimal microenvironment with imbalance of growth factors, nutrients, or oxygen can slow G1 progression (3). Therefore, individual cancer cells within a tumor are thought to vary significantly in their proliferative rate depending on the precise balance of these intrinsic and extrinsic factors. Interestingly, however, many tumor-derived cancer cell lines also produce slowly proliferating cells. These established lines have many acquired mutations that drive cell proliferation. They have also been grown ex vivo for years in a stable microenvironment to promote unbridled proliferation. These factors ought to favor a strong purifying selection against slow proliferators. We worked to understand how slowly proliferating cells seem to arise paradoxically in cancer cell lines.Results G0-Like Cancer Cells in Vitro. We began by studying MCF7, a highly proliferative, aneuploid, ER + /HER2 − human breast cancer cell line. This line displays significant proliferative heterogeneity despite mutations in CDKN2A and PIK3CA that cooperatively drive cell-cycle progression (4). We first hypothesized that slowly proliferating MCF7 cells might produce low levels of reactive oxygen species (ROS). This hypothesis was based on previous observations that slowly cycling hematopoietic, neural, and breast adult stem cells and cancer stem cells produce low levels of ROS (5-7). We stained MCF7 cells with 5-(and-6)chloromethyl 1-2′,7′-dichlorohydrofluorescein diacet...

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Section: G0-like Cancer Cells In Vitromentioning

confidence: 60%

Asymmetric cancer cell division regulated by AKT

Dey‐Guha

Wolfer

Yeh

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

128

120

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“…Two classes of inhibitors are currently in clinical development: catalytic, ATP-competitive inhibitors (such as GDC-0068) that preferentially target the active kinase, and allosteric inhibitors (such as MK-2206) that bind to the Akt plekstrin-homology domain, resulting in a conformational change that prevents Akt membrane localization and subsequent activation (15,16). GDC-0068, a potent, orally bioavailable, selective pan-Akt inhibitor, was identified by structure-guided drug design (17).…”

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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“…When polarity and hydrogen bond donating functionalities are added directly to the naphthyridine, further improvement is obtained. The 1,6-naphthyridin-5-one (27) is a potent and dual inhibitor of Akt1 and 2 and selective over Akt3, with IC 50 s of 3.5, 42 and 1900 nM, respectively [52]. It exhibits in cell assays more potent Akt1 activity relative to that of Akt 2 with IC 50 of 16 and 266 nM, respectively.…”

Section: Quinoxaline Naphthyridine and Pyrido-pyrimidine Derivativesmentioning

confidence: 99%

Non-ATP Competitive Protein Kinase Inhibitors

Garuti¹,

Roberti²,

Bottegoni

2010

CMC

112

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Protein kinases represent an attractive target in oncology drug discovery. Most of kinase inhibitors are ATP-competitive and are called type I inhibitors. The ATP-binding pocket is highly conserved among members of the kinase family and it is difficult to find selective agents. Moreover, the ATP-competitive inhibitors must compete with high intracellular ATP levels leading to a discrepancy between IC50s measured by biochemical versus cellular assays. The non-ATP competitive inhibitors, called type II and type III inhibitors, offer the possibility to overcome these problems. These inhibitors act by inducing a conformational shift in the target enzyme such that the kinase is no longer able to function. In the DFG-out form, the phenylalanine side chain moves to a new position. This movement creates a hydrophobic pocket available for occupation by the inhibitor. Some common features are present in these inhibitors. They contain a heterocyclic system that forms one or two hydrogen bonds with the kinase hinge residue. They also contain a hydrophobic moiety that occupies the pocket formed by the shift of phenylalanine from the DFG motif. Moreover, all the inhibitors bear a hydrogen bond donor-acceptor pair, usually urea or amide, that links the hinge-binding portion to the hydrophobic moiety and interacts with the allosteric site. Examples of non ATP-competitive inhibitors are available for various kinases. In this review small molecules capable of inducing the DFG-out conformation are reported, especially focusing on structural feature, SAR and biological properties.

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Allosteric inhibitors of Akt1 and Akt2: A naphthyridinone with efficacy in an A2780 tumor xenograft model

Cited by 71 publications

References 16 publications

Asymmetric cancer cell division regulated by AKT

Asymmetric cancer cell division regulated by AKT

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

Non-ATP Competitive Protein Kinase Inhibitors

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