Rapid Evolution of 6-Phenylpurine Inhibitors of Protein Kinase B through Structure-Based Design

Donald, Alastair; McHardy, T.; Rowlands, Martin; Hunter, Lisa Jane K.; Davies, Thomas G.; Berdini,; Boyle, R. G; Aherne, G. Wynne; Garrett, Michelle D.; Collins, Ian

doi:10.1021/jm0700924

Cited by 60 publications

(60 citation statements)

References 24 publications

(57 reference statements)

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“…The first approach involves screening direct binding inhibitors targeted to the ATP binding site of Akt. Example compounds include GSK690693 (51), 6-phenylpurines (52), and conjugates of oligoarginine peptides with adenine, adenosine, adenosine-5Ј-carboxylic acid, and 5-isoquinolinesulfonic acid (53). Although these compounds displayed strong inhibitory effects, other side effects would be expected due to non-selectivity because most kinases share a conserved amino acid sequence in the ATP binding site.…”

Section: Discussionmentioning

confidence: 99%

Akt Cys-310-targeted Inhibition by Hydroxylated Benzene Derivatives Is Tightly Linked to Their Immunosuppressive Effects

Lee

et al. 2010

Journal of Biological Chemistry

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The hydroxylated benzene metabolite hydroquinone (HQ) is mainly generated from benzene, an important industrial chemical, and is also a common dietary component. Although numerous reports have addressed the tumorigenesis-inducing effects of HQ, few papers have explored its molecular regulatory mechanism in immunological responses. In this study we characterized Akt (protein kinase B)-targeted regulation by HQ and its derivatives, in suppressing inflammatory responses using cellular, molecular, biochemical, and immunopharmacological approaches. HQ down-regulated inflammatory responses such as NO production, surface levels of pattern recognition receptors, and cytokine gene expression with IC 50 values that ranged from 5 to 10 M. HQ inhibition was mediated by blocking NF-B activation via suppression of its translocation pathway, which is composed of Akt, IB␣ kinase ␤, and IB␣. Of the targets in this pathway, HQ directly targeted and bound to the sulfhydryl group of Cys-310 of Akt and sequentially interrupted the phosphorylation of both Thr-308 and Ser-473 by mediation of ␤-mercaptoethanol, according to the liquid chromatography/ mass spectroscopy analysis of the interaction of HQ with an Aktderived peptide. Therefore, our data suggest that Akt and its target site Cys-310 can be considered as a prime molecular target of HQ-mediated immunosuppression and for novel antiAkt-targeted immunosuppressive drugs.

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Section: Discussionmentioning

confidence: 99%

Akt Cys-310-targeted Inhibition by Hydroxylated Benzene Derivatives Is Tightly Linked to Their Immunosuppressive Effects

Lee

et al. 2010

Journal of Biological Chemistry

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“…Recently, the PI3K/AKT signal transduction pathway has become the focus of intense interest as a critical regulator of tumor cell survival, and a number of AKT pathway inhibitors have been disclosed with a wide variety of potencies and specificities (2,44,45). In this report, we describe the in vitro and in vivo effects of AT7867, a recently developed inhibitor of AKT and p70S6K, which has been identified using fragment-based lead discovery and structure-based design technologies (29)(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

“…These fragments were validated by structural studies and rapidly transformed into potent lead compounds using structure-based design to increase the efficiency of the medicinal chemistry. This research was recently described in detail and has identified potent, low molecular weight inhibitors of AKT that exhibit drug-like properties (29)(30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

AT7867 Is a Potent and Oral Inhibitor of AKT and p70 S6 Kinase That Induces Pharmacodynamic Changes and Inhibits Human Tumor Xenograft Growth

Grimshaw

Hunter

Yap

et al. 2010

Molecular Cancer Therapeutics

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The serine/threonine kinase AKT plays a pivotal role in signal transduction events involved in malignant transformation and chemoresistance and is an attractive target for the development of cancer therapeutics. Fragment-based lead discovery, combined with structure-based drug design, has recently identified AT7867 as a novel and potent inhibitor of both AKT and the downstream kinase p70 S6 kinase (p70S6K) and also of protein kinase A. This ATP-competitive small molecule potently inhibits both AKT and p70S6K activity at the cellular level, as measured by inhibition of GSK3β and S6 ribosomal protein phosphorylation, and also causes growth inhibition in a range of human cancer cell lines as a single agent. Induction of apoptosis was detected by multiple methods in tumor cells following AT7867 treatment. Administration of AT7867 (90 mg/kg p.o. or 20 mg/kg i.p.) to athymic mice implanted with the PTEN-deficient U87MG human glioblastoma xenograft model caused inhibition of phosphorylation of downstream substrates of both AKT and p70S6K and induction of apoptosis, confirming the observations made in vitro. These doses of AT7867 also resulted in inhibition of human tumor growth in PTEN-deficient xenograft models. These data suggest that the novel strategy of AKT and p70S6K blockade may have therapeutic value and supports further evaluation of AT7867 as a singleagent anticancer strategy.

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“…[85,[88][89][90][91][92][93] Suzuki couplings have been used to introduce various substituted aryl groups into purine systems. [89,94] However, unprotected halo-9H-purine bases proved to be unreactive in common cross-coupling protocols, due to removal of the N9 proton.…”

Section: Suzuki Cross-coupling Of N-heterocyclesmentioning

confidence: 99%

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

Fleckenstein

Plenio

2008

Chemistry A European J

121

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A dicyclohexyl(2-sulfo-9-(3-(4-sulfophenyl)propyl)-9H-fluoren-9-yl)phosphonium salt was synthesized in 64% overall yield in three steps from simple commercially available starting materials. The highly water-soluble catalyst obtained from the corresponding phosphine and [Na(2)PdCl(4)] enabled the Suzuki coupling of a broad variety of N- and S-heterocyclic substrates. Chloropyridines (-quinolines) and aryl chlorides were coupled with aryl-, pyridine- or indoleboronic acids in quantitative yields in water/n-butanol solvent mixtures in the presence of 0.005-0.05 mol % of Pd catalyst at 100 degrees C, chloropurines were quantitatively Suzuki coupled in the presence of 0.5 mol % of catalyst, and S-heterocyclic aryl chlorides and aryl- or 3-pyridylboronic acids required 0.01-0.05 mol % Pd catalyst for full conversion. The key to the high activity of the Pd-phosphine catalyst is the rational design of the reaction parameters (i.e., the presence of water in the reaction mixture, good solubility of reactants and catalyst in n-butanol/water (3:1), and the electron-rich and sterically demanding nature of the phosphine ligand).

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Rapid Evolution of 6-Phenylpurine Inhibitors of Protein Kinase B through Structure-Based Design

Cited by 60 publications

References 24 publications

Akt Cys-310-targeted Inhibition by Hydroxylated Benzene Derivatives Is Tightly Linked to Their Immunosuppressive Effects

Akt Cys-310-targeted Inhibition by Hydroxylated Benzene Derivatives Is Tightly Linked to Their Immunosuppressive Effects

AT7867 Is a Potent and Oral Inhibitor of AKT and p70 S6 Kinase That Induces Pharmacodynamic Changes and Inhibits Human Tumor Xenograft Growth

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

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