Discovery of 3-oxabicyclo[4.1.0]heptane, a non-nitrogen containing morpholine isostere, and its application in novel inhibitors of the PI3K-AKT-mTOR pathway.

doi:10.1021/acs.jmedchem.9b00348

Paper

Discovery of 3-oxabicyclo[4.1.0]heptane, a non-nitrogen containing morpholine isostere, and its application in novel inhibitors of the PI3K-AKT-mTOR pathway.

Published Jul 8, 2019 · H. Hobbs, G. Bravi, I. Campbell

Journal of medicinal chemistry

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Abstract

4-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a co-planar conformation with an adjacent aromatic core favoured by the morpholine nitrogen non-bonding pair of electrons interacting with the electron deficient pyrimidine π-system. Few selective morpholine replacements have been identified to date. Herein we describe the discovery of a potent non-nitrogen containing morpholine isostere, with the ability to mimic this conformation and its application in a potent selective dual inhibitor of mTORC1 and mTORC2 [26b].

Study Snapshot

3-oxabicyclo[4.1.0]heptane, a non-nitrogen containing morpholine isostere, has been identified as a potent selective dual inhibitor of mTORC1 and mTORC2 in the PI3K-AKT-mTOR pathway.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Discovery of 3-oxabicyclo[4.1.0]heptane, a non-nitrogen containing morpholine isostere, and its application in novel inhibitors of the PI3K-AKT-mTOR pathway.

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References

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mTOR-mediated signaling plays a crucial role in regulating cell migration and survival in various cancers, with potential therapeutic implications in chronic lymphocytic leukemia.

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PIKK proteins play a role in regulating inflammation and immune responses, particularly through DNA damage and innate immune response pathways.

Twenty-five years of mTOR: Uncovering the link from nutrients to growth

The mTOR pathway is the key link between nutrient availability and growth regulation in animals, playing a central role in physiology, metabolism, aging, and common diseases.

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