Discovery of Potent and Selective Inhibitors of the Mammalian Target of Rapamycin (mTOR) Kinase

Nowak, Paweł; Cole, Derek C.; Brooijmans, Natasja; Bursavich, Matthew G.; Curran, Kevin J.; Ellingboe, John W.; Gibbons, James J.; Hollander, Irwin; Hu, Yongbo; Kaplan, Joshua; Malwitz, David J.; Toral‐Barza, Lourdes; Verheijen, Jeroen C.; Zask, Arie; Zhang, Weiguo; Yu, Ker

doi:10.1021/jm9012642

Cited by 49 publications

(43 citation statements)

References 30 publications

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“…The ATP-competitive inhibitors of mTOR were taken from the literature [18][19][20]. These molecules were built, hydrogens were added, and the structures were minimized in the Minimization module using the steepest descent and conjugate gradient methods in Discovery Studio 2.1.…”

Section: Pharmacophore Generationmentioning

confidence: 99%

“…Another inhibitor of mTOR, Ku-0063794, has been shown to have high specificity for mTOR compared to other lipid kinases [19]. Nowak et al and Zask et al modeled the structure of mTOR based on the crystal structure of PI3γ kinase in order to study the binding modes of inhibitors [20,21]. Nowak et al used highthroughput screening to identify mTOR inhibitors that, upon optimization, yielded selective mTOR inhibitors with high affinity compared to PI3α kinase.…”

Section: Introductionmentioning

confidence: 99%

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Ligand-based 3-D pharmacophore generation and molecular docking of mTOR kinase inhibitors

Tanneeru

Guruprasad

2011

J Mol Model

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The 3-D structure of the human mTOR kinase domain was modeled based on the crystal structure of PI3Kγ using comparative modeling methods, and the ATP-binding site of mTOR was characterized. The mTOR kinase 3-D model structure is similar to the structure of the PI3Kγ kinase domain, and exhibits great similarity to PI3Kγ at the active site of the kinase. Pharmacophore generation, the docking of mTOR inhibitors, and molecular dynamics (MD) simulations of mTOR-inhibitor docked complexes were carried out in this work. The best pharmacophore model generated from 27 ATP-competitive mTOR inhibitors comprised two hydrogen-bond acceptors, one aromatic ring, and one hydrophobic feature. These 27 inhibitors were docked into the ATP-binding site comprising the DFG motif, and the interactions in each protein-inhibitor complex were characterized. Mapping the pharmacophore model onto the docked inhibitors explained the specificity of the features of the pharmacophore and how they were arranged inside the active site of mTOR kinase. MD studies revealed important structural features, such as the large hydrophobic pocket "HP" and hydrophilic pocket "A1," and the solvent-exposed hydrophilic pocket "A2" at the active site of mTOR. Our results provide structural models of mTOR-inhibitor complexes and clues that should aid in the design of better mTOR kinase inhibitors.

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Section: Pharmacophore Generationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ligand-based 3-D pharmacophore generation and molecular docking of mTOR kinase inhibitors

Tanneeru

Guruprasad

2011

J Mol Model

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“…Several docking studies analysed the binding of mTOR inhibitors in the ATP-binding pocket [31,32,34]. The cocrystal structures of mTOR N -mLST8 with Torin-2, PP242 and PI-103 now reveal that, although the overall orientation of the inhibitors in the binding pocket was predicted correctly, their detailed binding modes diverged from the docked models.…”

Section: Discussionmentioning

confidence: 99%

“…Before the crystal structure was available, attempts had been made to model the catalytic domain and the ATPbinding site of mTOR, on the basis of structural homology with PI3Ks (phosphoinositide 3-kinases) [31,32]. The model of the mTOR kinase domain included the FRB and kinase domains (residues 1879-2549) and was built based on the then available structure of PI3KCγ [31,33].…”

Section: Introductionmentioning

confidence: 99%

Conserved sequence motifs and the structure of the mTOR kinase domain

Sauer

Imseng

Maier

et al. 2013

Biochemical Society Transactions

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The atypical serine/threonine kinase mTOR (mammalian target of rapamycin) is a central regulator of cell growth and metabolism. mTOR is part of two multisubunit signalling complexes, mTORC1 and mTORC2. Although many aspects of mTOR signalling are understood, the lack of high-resolution structures impairs a detailed understanding of complex assembly, function and regulation. The structure of the kinase domain is of special interest for the development of mTOR inhibitors as anti-cancer agents. A homology model of the mTOR kinase domain was derived from the structure of PI3Ks (phosphoinositide 3-kinases). More recently, the crystal structure of the catalytic domain of human mTOR was determined, providing long-awaited structural insight into the architecture of mTOR. Interestingly, the homology model predicted several aspects of the crystal structure. In the present paper, we revisit the homology model in the context of the now available crystal structure of the mTOR kinase domain.

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“…However, rapamycin and its analogs failed to provide a significant improvement of response in leukemia patients [87], most likely due to the negative feedback loops. The elevation of RTK-PI3K-PDK1 activity in response to rapamycin can promote Akt phosphorylation on Thr308, which may be sufficient for cell survival [88].…”

Section: Targeting Mtor Signaling For Leukemia Therapymentioning

confidence: 99%