- Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure–Activity Relationship, Biostructural, and Kinetic Insight
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The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more “drug-like” properties. Importantly, enzyme kinetic evaluation revealed a slow, tight-binding mechanism of inhibition, which is unprecedented for SIRT5. This is important information when applying inhibitors to probe mechanisms in biology.
- Rajabi, Nima,Auth, Marina,Troelsen, Kathrin R.,Pannek, Martin,Bhatt, Dhaval P.,Fontenas, Martin,Hirschey, Matthew D.,Steegborn, Clemens,Madsen, Andreas S.,Olsen, Christian A.
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p. 14836 - 14841
(2017/11/10)
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- Derivatives of 1-amino-1-(hetero)arylaminocarbonyl-6-hydroxyaminocarbonylhexane useful in the treatment of tumors
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The present invention provides the compound having the formula: wherein each of R1 and R2 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, t-butyl, aryloxy, arylalkyloxy, or pyr
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Paragraph 0059; 0060; 0109
(2015/11/11)
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- Heterocycle Derivatives As Histone Deacetylase (Hdac) Inhibitors
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The present invention relates to compounds of formula I: or pharmaceutically acceptable salts or tautomers thereof, which are inhibitors of histone deacetylase (HDAC). The compounds of the present invention are useful for treating cellular proliferative diseases, including cancer. Further, the compounds of the present invention are useful for treating neurodegenerative diseases, schizophrenia and stroke among other diseases.
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Page/Page column 90
(2009/03/07)
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