But these new findings suggest the possibility that the so-far-unparalleled specificity of the epoxyketone pharmacophore for the proteasome’s catalytic threonine residues can be extended to other classes of proteasome inhibitors yet to be developed

But these new findings suggest the possibility that the so-far-unparalleled specificity of the epoxyketone pharmacophore for the proteasome’s catalytic threonine residues can be extended to other classes of proteasome inhibitors yet to be developed. Importantly, they indicate that the second electrophile of a dual-electrophilic pharmacophore can be placed not one carbon, but two carbons, away from the first (i.e., in the position) to promote formation of the kinetically-favored seven-membered ring.[6] One might envision, for example, generating inhibitors analogous to the peptide halomethyl ketone cysteine/serine protease inhibitors but in which the leaving group is attached to the carbon instead of to the carbon. diverges from the previously-reported formation of the 1,4-morpholino adduct and indicates that, in the second step of the inhibitory reaction, the N-terminal amino group of the proteasome’s catalytic threonine attacks the carbon, rather than the carbon, of the inhibitor’s epoxide (Figure 2).[3c, 3d, 5b, 6] Schrader et al also indicated that the peptide ketoaldehyde inhibitor Z-LLY-ketoaldehyde forms a 1,4-morpholino adduct with 5’s catalytic threonine residue, contrasting the 5,6-dihydro-2H-1,4-oxazino ring product AMG 837 sodium salt proposed by Gr?wert et al.[6-7] Through cluster quantum chemical calculations and kinetic assays, Schrader et al further evaluated the differences between the inhibitory reactions that form six-membered versus seven-membered rings.[6] Based on the calculated pathways of these reactions, they identified the cyclization step as the bottleneck of both reactions. Their results also indicated that, although the six-membered ring product is more thermodynamically stable than the seven-membered ring product, the greater strain of the transition state of the former pathway causes the latter pathway to be AMG 837 sodium salt favored from a kinetic standpoint. The results of kinetic assays also support that seven-membered ring formation is kinetically favored over six-membered ring formation. The contributions of Schrader et al provide important insight for proteasome inhibitor design. Currently, the clinical UVO development of proteasome inhibitors remains limited to inhibitors falling within the peptide boronic acid or peptide epoxyketone classes, as they are regarded as having acceptably low activity against non-proteasomal proteases. But these new findings AMG 837 sodium salt suggest the possibility that the so-far-unparalleled specificity of the epoxyketone pharmacophore for the proteasome’s catalytic threonine residues can be extended to other classes of proteasome inhibitors yet to be developed. Importantly, they indicate that the second electrophile of a dual-electrophilic pharmacophore can be placed not one carbon, but two carbons, away from the first (i.e., in the position) to promote formation of the kinetically-favored seven-membered ring.[6] One might envision, for example, generating inhibitors analogous to the peptide halomethyl ketone cysteine/serine protease inhibitors but in which the leaving group is attached to the carbon instead of to the carbon. Exploration of these possibilities may yield inhibitors with improved proteasome selectivity relative to peptide boronic acids and improved pharmacokinetic profiles over those of peptide epoxyketones. It is hoped that such improvements would in turn lead to enhanced AMG 837 sodium salt anticancer efficacy and reduced toxicity, thereby benefiting patients with multiple myeloma as well as those with other types of cancer. Acknowledgements We would lke to thank the National Institutes of Health (grant R01 CA188354 to AMG 837 sodium salt K.B.K.) and Basic Science Research Program, National Research Foundation of Korea, Ministry of Science, ICT and Future Planning (NRF-2014R1A1A3050645 to W.L.) for financially supporting this work..

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