Discovery of a novel protein kinase B inhibitor by structure-based virtual screening

Medina‐Franco, José L.; Giulianotti, Marc A.; Yu, Yongping; Shen, Liangliang; Yao, Libo; Singh, Narender

doi:10.1016/j.bmcl.2009.06.078

Cited by 18 publications

(19 citation statements)

References 23 publications

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“…Compound 11 was the top ranked molecule in docking and our next goal is to optimize its activity. Based on previous results (13) and molecular modeling studies discussed in this work, we hypothesize that the crystal structure of AKT‐2 in complex with 9 can be used to conduct the structure‐guided optimization of 11 .…”

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confidence: 73%

“…A crystal structure of the AKT‐2 in complex with compound 9 has been published (10). As part of our on‐going effort involving anticancer drug discovery (13–15), we recently reported the discovery of the low micromolar AKT‐2 inhibitor 11 with a distinct scaffold (Figure 1) (13). In that work, we conducted a multistep docking‐based virtual screening of a large compound database with the crystal structure of AKT‐2 in complex with 9 .…”

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confidence: 99%

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Docking of Protein Kinase B Inhibitors: Implications in the Structure‐Based Optimization of a Novel Scaffold

et al. 2010

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Protein kinase B (PKB ⁄ AKT) is an attractive therapeutic target in anticancer drug development. We have recently identified by docking-based virtual screening a low micromolar AKT-2 inhibitor. Additionally, the virtual screening hit represents a novel AKT-2 inhibitor scaffold. In this work, we discuss a structure-based design strategy toward the optimization of this hit. Following this strategy and using a herein validated docking protocol, we conducted the design of novel compounds with expected improved activity over the parent compound. The newly designed molecules have high predicted affinity for AKT-2; are synthetically accessible and are contained within the kinase-relevant property space.Key words: AKT, cancer, drug design, structure-activity relationships Abbreviations: HBA, hydrogen bond acceptors; HBD, hydrogen bond donors; IFD, induce-fit docking; MOE, molecular operating environment; MW, molecular weight; RB, number of rotatable bonds; SAR, structure-activity relationships; TPSA, topological surface area; XP, extra precision. The serine ⁄ threonine kinase B, also known as AKT, has several downstream targets that regulate a number of processes associated with cell growth, differentiation and division. AKT is frequently amplified and over-expressed in human cancer cells and its inhibition is a promising therapeutic approach for the treatment of cancers (1,2). There are three known subtypes, AKT-1 ⁄ PKBa, AKT-2 ⁄ PKBb and AKT-3 ⁄ PKBc. Each one is associated with different types of cancers. In particular, AKT-2 is amplified in pancreatic, breast and ovarian tumors. AKT-3 is over expressed in hormoneinsensitive breast and prostate cancers (1). Aberrations in AKT-1 are less common. AKT has an N-terminal pleckstrin homology domain, a hinge region, a central kinase domain, and a C-terminal region (3). The kinase domains have a large similarity of more than 85% and the binding pocket residues are the same (3,4). To date, small molecules targeting the ATP-binding site in the kinase domain, and allosteric inhibitors interfering with the pleckstrin homology domain function have been reported, among others (3-6). AKT inhibitors, either ATP competitors or compounds that interact with regulatory domains, have shown promising activity in cancer treatment. It is thought that subtype-selective inhibitors are needed for optimal efficacy with acceptable toxicity (1). However, it remains to be determined if subtype selective inhibitors have a larger therapeutic window over compounds that inhibit all three subtypes (4). For example, a pan-AKT inhibitor with nanomolar activity against the three subtypes has been evaluated as an intravenous agent in clinical trials in patients with cancer (7). Small molecules targeting the ATP-binding site have been reported. These include isoquinoline-5-sulfonamides (8,9), pyrazole (see below), (10) indazole (11) and aminofurazan analogs (7). Several of these inhibitors haven been developed using structure-based design techniques and are reviewed in Ref. (4). Despite the fact that some c...

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Docking of Protein Kinase B Inhibitors: Implications in the Structure‐Based Optimization of a Novel Scaffold

et al. 2010

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“…Most inhibitors identified to date are nonselective among individual isoforms. A new compound was recently reported for serving as a basis for structure–activity-based design of Akt2-selective compounds [89]. The development of more potent and selective competitive small-molecule inhibitors for Akt isoforms may, thus, help to determine whether any of the individual Akt isoforms are a viable target for thrombosis.…”

Section: Akt Pathways and Drug Developmentmentioning

confidence: 99%

Akt signaling in platelets and thrombosis

Woulfe

2010

Expert Review of Hematology

122

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Akt is a Ser-Thr kinase with pleiotropic effects on cell survival, growth and metabolism. Recent evidence from gene-deletion studies in mice, and analysis of human platelets treated with Akt inhibitors, suggest that Akt regulates platelet activation, with potential consequences for thrombosis. Akt activation is regulated by the level of phosphoinositide 3-phosphates, and proteins that regulate concentrations of this lipid also regulate Akt activation and platelet function. Although the effectors through which Akt contributes to platelet activation are not definitively known, several candidates are discussed, including endothelial nitric oxide synthase, glycogen synthase kinase 3β, phosphodiesterase 3A and the integrin β 3 tail. Selective inhibitors of Akt isoforms or of proteins that contribute to its activation, such as individual PI3K isoforms, may make attractive targets for antithrombotic therapy. This review summarizes the current literature describing Akt activity and its regulation in platelets, including speculation regarding the future of Akt or its regulatory pathways as targets for the development of antithrombotic therapies. KeywordsAkt; glycogen synthase kinase3; PI3K; platelet; thrombosis Akt (also termed protein kinase B [PKB]) is a serine-threonine kinase that contributes to signaling and activation responses of human platelets, and has been shown to support thrombus formation in mouse models. These results have fueled speculation that Akt activation may be a contributing factor to thrombosis in humans. The recent identification of a single-nucleotide polymorphism (SNP) in the gene encoding Akt2 associated with reactivity of human platelets lends considerable weight to this idea [1], although direct association with prothrombotic consequences has yet to be demonstrated. Although no drugs targeting Akt are currently in trials for the management of thrombotic sequellae in at-risk patients, these studies suggest that some features of Akt signaling pathways might make attractive targets for antithrombotic therapy. However, none of the three Akt isoforms are entirely platelet specific, and all have diverse functions, so the direct targeting of individual isoforms as antithrombotic therapy raises significant concern regarding off-target effects. This review addresses our current understanding of the contribution of Akt isoforms to platelet function based upon studies of human platelets ex vivo and gene-targeting studies in mouse models of platelet activity and thrombosis.

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“…Protein kinase B (PKB/Akt) family members (PKBα/Akt1, PKBβ/Akt2, and PKBγ/Akt3) are considered vivid targets for the design and development of efficacious chemotherapeutics agents from the last two decades (Nicholson & Anderson, ). Previously, several small molecules or ATP competitors were designed to target the conserved ATP‐binding site in the kinase domain of the Akt subtypes such as aminofurazan‐derived inhibitor (Yap et al., ), isoquinoline‐5‐sulfonamides structural classes such as H‐89, indazole–pyridines, and pyrazole‐based compounds (Medina‐Franco et al., ). However, only limited numbers of inhibitory compounds entered into an early phase of clinical trials, as ATP competitors are unable to differentiate between ATP‐binding sites conserved in protein kinases and other ATP‐binding proteins (Cherrin et al., ; Huang, Zhou, Lafleur, Nevado & Caflisch, ).…”

Section: Introductionmentioning

confidence: 99%

Structure‐based pharmacophore models to probe anticancer activity of inhibitors of protein kinase B‐beta (PKB β)

et al. 2018

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Protein kinase B-beta (PKBβ/Akt2) is a non-receptor kinase that has attracted a great deal of attention as a promising cancer therapy drug target. In mammalian cells, hyperactivation of Akt2 exclusively facilitates the survival of solid tumors by interfering with cell cycle progression. This definite function of Akt2 in tumor survival/maintenance provides the basis for the development of its antagonists with the aim of desensitizing cell proliferation. In order to find novel and potent Akt2 inhibitors, structure-based pharmacophore models have been developed and validated by the test set prediction. The final pharmacophore model was used for hits identification using public chemical databases. The hits were further prioritized using drug-like filters which revealed 14 potential hit compounds having novel chemical scaffolds. Our results elucidate the importance of three hydrogen bond acceptors (A), one hydrogen bond donor (D), one hydrophobic group (H), and one positive ionic charge (P) toward inhibition of the Ak2. One of our selected hits showed 68% cell apoptosis at 8 μg/ml concentration. We proposed various chemical scaffolds including benzamide, carboxamide, and methyl benzimidazole targeting Akt2 and thus may act as potential leads for the further development of new anticancer agents. K E Y W O R D SAkt, ligand-protein interactions, phosphoinositide 3-kinase, quinoline-type inhibitors, structure-based pharmacophore modeling, virtual screening 326 | AKHTAR eT Al.

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Discovery of a novel protein kinase B inhibitor by structure-based virtual screening

Cited by 18 publications

References 23 publications

Docking of Protein Kinase B Inhibitors: Implications in the Structure‐Based Optimization of a Novel Scaffold

Docking of Protein Kinase B Inhibitors: Implications in the Structure‐Based Optimization of a Novel Scaffold

Akt signaling in platelets and thrombosis

Structure‐based pharmacophore models to probe anticancer activity of inhibitors of protein kinase B‐beta (PKB β)

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