Abstract
Kinase inhibitors capable of blocking the phosphorylation of protein substrates with high selectivity are essential to probe and elucidate the etiological role of such molecules and their signalling pathways.
Highlights
The mechanistic or mammalian target of rapamycin is a serine/threonine protein kinase that operates as the catalytic subunit of two essential protein complexes called mTORC1 and mTORC2.1 These complexes play a central role in several signal transduction cascades, acting as sensors that integrate multiple extracellular and intracellular signals to coordinate cell metabolism, proliferation, survival and migration.[1]
Medicinal chemistry campaigns on that scaffold have been mainly directed at the C3 position of the heterocycle, which have led to the discovery of inhibitors of different kinases, mostly tyrosine kinases e.g. SRC, ABL, RET, PDGFRs, IGF1R, VEGFRs or KIT,[16,17,18] and non-tyrosine kinases such as PI3Ks and mTOR.[7,18]
Many chemical probes are currently available, customized chemical design of target selectivity combined with careful characterization of their biochemical and phenotypic properties is uncommon, even if that is essential to confirm the accuracy of any biological conclusions.[26]
Summary
The mechanistic or mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that operates as the catalytic subunit of two essential protein complexes called mTORC1 and mTORC2.1 These complexes play a central role in several signal transduction cascades, acting as sensors that integrate multiple extracellular and intracellular signals to coordinate cell metabolism, proliferation, survival and migration.[1]. The novel compounds displayed high inhibition of mTOR, several fold superior to that of the lead compound 5, and good-to-excellent selectivity over other kinases, including PI3Ks, a subfamily of kinases known to be targeted by most mTOR kinase inhibitors.[12] While derivative (a.k.a. eCF309) exhibited slightly lower antiproliferative potency against MCF7 cells than and 14, it induced the strongest inhibition of mTOR kinase activity (IC50 = 15 nM) and displayed higher selectivity over PI3Ks. These results indicate that even small modifications at the acetal group of the N1 position of the ring can result in significant variations on the binding properties of the inhibitor.
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