Structural mechanisms of the mTOR pathway

Linde-Garelli, Karen Y.; Rogala, Kacper B.

doi:10.1016/j.sbi.2023.102663

Cited by 12 publications

(8 citation statements)

References 61 publications

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“…The reaction mixture was warmed up to rt and stirred for 6 h. The mixture was concentrated to give a crude isocyanate intermediate, which was redissolved in CH 2 Cl 2 (10 mL), then the corresponding substituted aniline was introduced, and the resulting mixture was stirred at rt under a N 2 atmosphere for 6 h. The mixture was concentrated under reduce pressure, and the residue was purified by column chromatography on silica gel (DCM/MeOH = 30:1) to afford the corresponding compound. Hz, 2H), 3.82 (s, 8H), 3.66 (s, 8H), and 1.56−1.46 (m, 9H); 13 (4,3,morpholine (17). 10 To a solution of 2,4,6-trichloro-1,3,5-triazine (13, 2.0 g, 10.8. mmol) in DCM (10 mL) were slowly added morpholine (0.43 mL, 5.0 mmol) and DIPEA (0.92 mL, 5.25 mmol) at −78 °C.…”

Section: Synthesis Of Compounds 15a−imentioning

confidence: 99%

“…Removing the solvent in vacuo, the residue was purified by column chromatography on silica gel (DCM/MeOH = 100:1 to 20:1) to provide the corresponding derivative 18. 4- (4-((4aR,7aR)-Hexahydro-6H- [1,4]dioxino [2,3-c]pyrrol-6-yl)-6morpholino-1,3,5-triazin-2-yl)aniline (19m). 27 Yellow solid, yield 85.1%.…”

Section: Synthesis Of Compounds 15a−imentioning

confidence: 99%

“…mTOR is recognized to form two distinct polyprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is also known as a rapamycin-sensitive protein, coordinating with the auxiliary protein Raptor to phosphorylate diverse substrates, including ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) . mTORC2 is characterized as a rapamycin-insensitive protein, consisting of mTOR, Protor, Rictor, Deptor, mLST8, and mSin1, which phosphorylates and activates Akt in response to cellular stimulation .…”

Section: Introductionmentioning

confidence: 99%

“…mTORC1 is also known as a rapamycin-sensitive protein, coordinating with the auxiliary protein Raptor to phosphorylate diverse substrates, including ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4EBP1). 4 mTORC2 is characterized as a rapamycin-insensitive protein, consisting of mTOR, Protor, Rictor, Deptor, mLST8, and mSin1, which phosphorylates and activates Akt in response to cellular stimulation. 4 In general, mTORC1 is a key regulator of cellular precancerous effects, whereas mTORC2 plays a crucial role in regulating the Akt survival pathway.…”

Section: ■ Introductionmentioning

confidence: 99%

“…4 mTORC2 is characterized as a rapamycin-insensitive protein, consisting of mTOR, Protor, Rictor, Deptor, mLST8, and mSin1, which phosphorylates and activates Akt in response to cellular stimulation. 4 In general, mTORC1 is a key regulator of cellular precancerous effects, whereas mTORC2 plays a crucial role in regulating the Akt survival pathway. The overactivation or overexpression of mTOR has been proven to be in close relation to the occurrence and development of many diseases, particularly in various malignant tumors.…”

Section: ■ Introductionmentioning

confidence: 99%

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Design, Synthesis, Formulation, and Bioevaluation of Trisubstituted Triazines as Highly Selective mTOR Inhibitors for the Treatment of Human Breast Cancer

Sun,

Chu,

Zhang

et al. 2024

J. Med. Chem.

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The aberrant activation of the PI3K/mTOR signaling pathway is implicated in various human cancers. Thus, the development of inhibitors targeting mTOR has attracted considerable attention. In this study, we used a structure-based drug design strategy to discover a highly potent and kinaseselective mTOR inhibitor 24 (PT-88), which demonstrated an mTOR inhibitory IC 50 value of 1.2 nM without obvious inhibition against another 195 kinases from the kinase profiling screening. PT-88 displayed selective inhibition against MCF-7 cells (IC 50 : 0.74 μM) with high biosafety against normal cells, in which autophagy induced by mTOR inhibition was implicated. After successful encapsulation in a lipodisc formulation, PT-88 demonstrated favorable pharmacokinetic and biosafety profiles and exerted a large antitumor effect in an MCF-7 subcutaneous bearing nude mice model. Our study shows the discovery of a highly selective mTOR inhibitor using a structure-based drug discovery strategy and provides a promising antitumor candidate for future study and development.

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Section: Synthesis Of Compounds 15a−imentioning

confidence: 99%

Section: Synthesis Of Compounds 15a−imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Design, Synthesis, Formulation, and Bioevaluation of Trisubstituted Triazines as Highly Selective mTOR Inhibitors for the Treatment of Human Breast Cancer

Sun,

Chu,

Zhang

et al. 2024

J. Med. Chem.

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Food for thought: Nutrient metabolism controlling early T cell development

Werlen,

Hernandez,

Jacinto

2024

BioEssays

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T cells develop in the thymus by expressing a diverse repertoire of either αβ‐ or γδ‐T cell receptors (TCR). While many studies have elucidated how TCR signaling and gene expression control T cell ontogeny, the role of nutrient metabolism is just emerging. Here, we discuss how metabolic reprogramming and nutrient availability impact the fate of developing thymic T cells. We focus on how the PI3K/mTOR signaling mediates various extracellular inputs and how this signaling pathway controls metabolic rewiring during highly proliferative and anabolic developmental stages. We highlight the role of the hexosamine biosynthetic pathway that generates metabolites that are utilized for N‐ and O‐linked glycosylation of proteins and how it impacts TCR expression during T cell ontogeny. We consider the dichotomy in metabolic needs during αβ‐ versus γδ‐T cell lineage commitment as well as how metabolism is also coupled to molecular signaling that controls cell fate.

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