A Small Molecule Inhibits Akt through Direct Binding to Akt and Preventing Akt Membrane Translocation

Kim, Donghwa; Sun, Mei; He, Lili; Zhou, Qinghua; Chen, Jun; Sun, X. F.; Bepler, Gerold; Sebti, Saı̈d M.; Cheng, Jin Q.

doi:10.1074/jbc.m109.094060

Cited by 48 publications

(30 citation statements)

References 44 publications

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“…Similar successes with cell-based screens were reported by Gumireddy et al with the discovery of the low nanomolar Plk1 (Polo-like kinase 1) inhibitor ON01910, which is currently in Phase I-II cancer trials [58]. Furthermore, the Akt2 inhibitor API-1, which is hypothesized to act by interfering with Akt2 membrane trans location (and therefore activation by PDK1) by blocking the PH-domain, originated from cellular screens using Akt2 transformed cells [59], illustrating the power of these types of cellular screens. Ultimately, the take home message is that discovering inhibitors with new mechanisms of action would be difficult to predict from in vitro screens that often utilize isolated catalytic domains and calls for the development of new approaches that marry in vitro and in cellulo screening strategies.…”

Section: Type IV Inhibitor: As Coinedmentioning

confidence: 63%

Tinkering Outside the Kinase ATP Box: Allosteric (Type IV) and Bivalent (Type V) Inhibitors of Protein Kinases

Cox

Shomin

Ghosh³

2010

Future Med. Chem.

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Many members of the protein kinase family have emerged as key targets for pharmacological intervention, most notably in cancer. However, the high sequence and structural homology shared by the more than 500 human protein kinases renders it exceedingly difficult to develop selective inhibitors. Most, if not all, existing inhibitors target multiple protein kinases. Current paradigm suggests that an inhibitor that targets multiple kinases and displays polypharmacology is not only acceptable but also often desirable as a therapeutic agent. However, as we move toward personalized medicine the currently acceptable promiscuity is likely to pose significant hurdles in terms of their therapeutic index, especially for diseases that necessitate long-term drug administration. Moreover, selective inhibitors are the only pharmacologically relevant route toward reagents for the dissection of complex signal transduction pathways. This article provides an overview of recent developments in the design of kinase inhibitors that display increasing selectivity by targeting regions outside the highly conserved ATP-binding pocket. These new approaches may pave the way to potentially new avenues for drug discovery while providing valuable tools for studying signal transduction.

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Section: Type IV Inhibitor: As Coinedmentioning

confidence: 63%

Tinkering Outside the Kinase ATP Box: Allosteric (Type IV) and Bivalent (Type V) Inhibitors of Protein Kinases

Cox

Shomin

Ghosh³

2010

Future Med. Chem.

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“…Recently, an analog of the antibiotic sangivamycin, herein called API-1, was identified as a novel AKT inhibitor [136] (Fig. 3B, compound 18 ).…”

Section: Inhibitors Of the Ph Domain Of Aktmentioning

confidence: 99%

Novel Inhibitors of AKT: Assessment of a Different Approach Targeting the Pleckstrin Homology Domain

Ej¹

2011

CMC

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Protein kinase B/AKT plays a central role in cancer. The serine/threonine kinase is overexpressed or constitutively active in many cancers and has been validated as a therapeutic target for cancer treatment. However, targeting the kinase activity has revealed itself to be a challenge due to non-selectivity of the compounds towards other kinases. This review summarizes other approaches scientists have developed to inhibit the activity and function of AKT. They consist of targeting the pleckstrin homology (PH) domain of AKT. Indeed, upon the generation of 3-phosphorylated phosphatidylinositol phosphates (PI3Ps) by PI3-kinase (PI3K), AKT translocates from the cytosol to the plasma membrane and binds to the PI3Ps via its PH domain. Thus, several analogs of PI3Ps (PI Analogs or PIAs), alkylphospholipids (APLs), such as edelfosine or inositol phosphates (IPs) have been described to inhibit the binding of the PH domain to PI3Ps. Recent allostetic inhibitors and small molecules that do not bind the kinase domain but affect the kinase activity of AKT, presumably by interacting with the PH domain, have been also identified. Finally, several drug screening studies spawned novel chemical scaffolds that bind the PH domain of AKT. Together, these approaches have been more or less sucessful in vitro and to some extent translated in preclinical studies. Several of these new AKT PH domain inhibitors exhibit promising anti-tumor activity in mouse models and some of them show synergy with ionizing radiation and chemotherapy. Early clinical trials have started and results will attest to the validity and efficacy of such approaches in the near future.

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“…3 A recently developed pan-AKT inhibitor (API-1) leads to cell growth arrest and apoptosis in cancer cells with elevated AKT activity. 4 API-1 also demonstrates an in vitro inhibitory effect on the constitutively active AKT1 E17K by direct binding to the pleckstrin homology domain and blocking of the membrane translocation of AKT1. 4 Consequently, identifying the subset of non-small cell lung cancer (NSCLC) patients with the AKT1 E17K mutation may be important for future therapeutic options.…”

mentioning

confidence: 99%

Rarity ofAKT1andAKT3E17K mutations in squamous cell carcinoma of lung

Do¹,

Salemi²,

Murone³

et al. 2010

Cell Cycle

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A Small Molecule Inhibits Akt through Direct Binding to Akt and Preventing Akt Membrane Translocation

Cited by 48 publications

References 44 publications

Tinkering Outside the Kinase ATP Box: Allosteric (Type IV) and Bivalent (Type V) Inhibitors of Protein Kinases

Tinkering Outside the Kinase ATP Box: Allosteric (Type IV) and Bivalent (Type V) Inhibitors of Protein Kinases

Novel Inhibitors of AKT: Assessment of a Different Approach Targeting the Pleckstrin Homology Domain

Rarity ofAKT1andAKT3E17K mutations in squamous cell carcinoma of lung

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