Allosteric inhibitors of Akt1 and Akt2: Discovery of [1,2,4]triazolo[3,4-f][1,6]naphthyridines with potent and balanced activity

Li, Yiwei; Liang, Jun; Siu, Tony; Hu, Essa; Rossi, Michael; Barnett, Stanley F.; Defeo-Jones, Deborah; Jones, Raymond E.; Robinson, R.; Leander, Karen; Huber, Hans E.; Mittal, Sachin; Cosford, Nicholas D. P.; Prasit, Peppi

doi:10.1016/j.bmcl.2008.12.017

Cited by 52 publications

(33 citation statements)

References 22 publications

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“…Ideally, selective inhibitors of Akt1 should be used for the treatment of prostate and endometrial cancers that display dysfunctional PTEN. The recent development of small-molecule inhibitors that preferentially inhibit Akt1 (Li et al , 2009; Lindsley, 2010) could address this issue.…”

Section: Discussionmentioning

confidence: 99%

“…The deletion of Akt2 elicits insulin resistance with a significant elevation of insulin levels (Cho et al , 2001a; Garofalo et al , 2003; Chen et al , 2009), but the haploinsufficiency Akt1 together with Akt2 deficiency elicits a severe diabetic phenotype (Chen et al , 2009). Because Akt is an attractive target for cancer therapy, and Akt-isoform-specific inhibitors are being developed (Li et al , 2009; Lindsley, 2010), it is important to know the effect of Akt-isoform-specific inhibition on tumor development.…”

Section: Introductionmentioning

confidence: 99%

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The effect Akt2 deletion on tumor development in Pten+/− mice

Jeon

et al. 2011

Oncogene

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The serine/threonine kinase Akt is frequently activated in human cancers and is considered an attractive therapeutic target. However, the relative contributions of the different Akt isoforms to tumorigenesis, and the effect of their deficiencies on cancer development are not well understood. We had previously shown that Akt1 deficiency is sufficient to markedly reduce the incidence of tumors in Pten+/− mice. Particularly, Akt1 deficiency inhibits endometrial carcinoma and prostate neoplasia in Pten+/− mice. Here, we analyzed the effect of Akt2 deficiency on the incidence of tumors in Pten+/− mice. Relative to Akt1, Akt2 deficiency had little-to-no effect on the incidence of prostate neoplasia, endometrial carcinoma, intestinal polyps and adrenal lesions in Pten+/− mice. However, Akt2 deficiency significantly decreased the incidence of thyroid tumors in Pten+/−, which correlates with the relatively high level of Akt2 expression in the thyroid. Thus, unlike Akt1 deletion, Akt2 deletion is not sufficient to markedly inhibit tumorigenesis in Pten+/− mice in most tested tissues. The relatively small effect of Akt2 deletion on the inhibition of tumorigenesis in Pten+/− mice could be explained, in part, by an insufficient decrease in total Akt activity, due to the relatively lower Akt2 versus Akt1 expression, and relatively high blood insulin levels in Pten+/−Akt2−/− mice. The relatively high blood insulin levels in Pten+/−Akt2−/− mice may elevate the activity of Akt1, and possibly Akt3, thus, limiting the reduction of total Akt activity and preventing this activity from dropping to a threshold level required to inhibit tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The effect Akt2 deletion on tumor development in Pten+/− mice

Jeon

et al. 2011

Oncogene

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“…Addition of the triazole fused to 1,6-naphthyridine results in the tricyclic derivative (28) that exhibits IC 50 of 4 and 10 nM against Akt1 and 2, respectively. It shows a good cellular activity that leads to inhibition of Akt 1 and 2 in vivo in a mouse model [53].…”

Section: Quinoxaline Naphthyridine and Pyrido-pyrimidine Derivativesmentioning

confidence: 99%

Non-ATP Competitive Protein Kinase Inhibitors

Garuti¹,

Roberti²,

Bottegoni

2010

CMC

111

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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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“…Following these initial disclosures, Merck published seven manuscripts during 2008 – 2009 describing additional refinements to their allosteric Akt inhibitors [155–161], culminating in a successful oral Phase I trial with MK-2206 74 . The first manuscript described 69 , a congener of 62 with improved aqueous solubility and balanced biochemical and cell-based activity [155].…”

Section: Small Molecule Akt Inhibitorsmentioning

confidence: 99%

“…A series of pyridopyrimidines soon followed, such as 72 , and SAR efforts addressed hERG liabilities [160]. The most recent primary literature report describes a series of [1,2,4]triazolo[3,4-f][1,6]naphthyridines, exemplified by 73 , with potent and balanced Akt inhibition properties and devoid of hERG liabilities [161]. Further optimization and truncation led to MK-2206 74 (Akt1 IC 50 = 8 nM, Akt2 IC 50 = 12 nM, Akt3 IC 50 = 65 nM).…”

Section: Small Molecule Akt Inhibitorsmentioning

confidence: 99%

Inhibition of Akt with small molecules and biologics: historical perspective and current status of the patent landscape

Mattmann

Stoops

Lindsley

2011

Expert Opinion on Therapeutic Patents

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Introduction Akt plays a pivotal role in cell survival and proliferation through a number of downstream effectors; unregulated activation of the PI3K/PTEN/Akt pathway is a prominent feature of many human cancers. Akt is considered an attractive target for cancer therapy by the inhibition of Akt alone or in combination with standard cancer chemotherapeutics. Both preclinical animal studies and clinical trials in humans have validated Akt as an important target of cancer drug discovery. Area covered A historical perspective of Akt inhibitors, including PI analogs, ATP-competitive and allosteric Akt inhibitors, along with other inhibitory mechanisms are reviewed in this paper with a focus on issued patents, patent applications and a summary of clinical trial updates since the last review in 2007. Expert opinion A vast diversity of inhibitors of Akt, both small molecule and biologic, have been developed in the past 5 years, with over a dozen in various phases of clinical development, and several displaying efficacy in humans. While it is not yet clear which mechanism of Akt inhibition will be optimal in humans, or which Akt isoforms to inhibit, or whether a small molecule or biologic agent will be best, data to all of these points will be available in the near future.

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Allosteric inhibitors of Akt1 and Akt2: Discovery of [1,2,4]triazolo[3,4-f][1,6]naphthyridines with potent and balanced activity

Cited by 52 publications

References 22 publications

The effect Akt2 deletion on tumor development in Pten+/− mice

The effect Akt2 deletion on tumor development in Pten+/− mice

Non-ATP Competitive Protein Kinase Inhibitors

Inhibition of Akt with small molecules and biologics: historical perspective and current status of the patent landscape

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