Adenosine Mimetics as Inhibitors of NAD⁺-Dependent Histone Deacetylases, from Kinase to Sirtuin Inhibition

Abstract

NAD+-dependent histone deacetylases, sirtuins, cleave acetyl groups from lysines of histones and other proteins to regulate their activity. Identification of potent selective inhibitors would help to elucidate sirtuin biology and could lead to useful therapeutic agents. NAD+ has an adenosine moiety that is also present in the kinase cofactor ATP. Kinase inhibitors based upon adenosine mimesis may thus also target NAD+-dependent enzymes. We present a systematic approach using adenosine mimics from one cofactor class (kinase inhibitors) as a viable method to generate new lead structures in another cofactor class (sirtuin inhibitors). Our findings have broad implications for medicinal chemistry and specifically for sirtuin inhibitor design. Our results also raise a question as to whether selectivity profiling for kinase inhibitors should be limited to ATP-dependent targets.

An integrated on‐chip sirtuin assay

“…Taking into account that the standard deviation is about 2% as shown above the decrease of the product signal in the presence of an inhibitor can be regarded as significant. Additionally it can be stated that Ro 31-8220 is a more effective inhibitor for hSIRT1 than GF 109203X which is in agreement with the literature [20,33]. When the on-chip reaction was performed in presence of sirtinol no inhibition was observed.…”

“…Moreover, we evaluated the applicability of the system to the screening of inhibitors. For these proof of principle experiments three known inhibitors for sirtuin enzymes were chosen, namely GF 109203X [33], Ro 31-8220 [33] and sirtinol [34]. Inhibition studies were carried out by adding 200 µM of the respective inhibitor to the substrate solution.…”

Synthesis and structural peculiarities of gallium Complexes with novel paullone derivatives

“…While an underivatized lactam unit is essential for CDK inhibition for steric complementarity reasons [3], a lactam-substituted paullone was discovered quite recently to inhibit sirtuins (SIRT; NAD + -dependent deacetylases), which are likely involved in the pathogenesis of viral diseases and cancer [4]. Since lactams could be converted into amidines and hydrazones providing a binding site for metals, the synthesis of ruthenium complexes with 9-bromo-6-(α-picolylamino)-7,12-dihydroindolo [3,2-d][1]benzazepine (1, Fig.…”

A Novel Chalcone Polyphenol Inhibits the Deacetylase Activity of SIRT1 and Cell Growth in HEK293T Cells

“…Several hydrogen-bond donors, for example, hydroxyl groups, have been suggested to be important for an inhibitor to interact with a putative SIRT2 active site (29,30). As the site is highly conserved in SIRT1, it is assumed that there are some polyphenols where the location of the hydroxyl groups is potentially suitable for the interaction with SIRT1 at the putative active site.…”

“…Sirtinol, splitomicin, some kinds of indoles and their derivatives have been identified as inhibitors of sirtuins by using a phenotypic screen in yeast and an in vitro deacetylation assay (23 -28). In addition, some compounds were characterized as inhibitors of sirtuins by applying molecular modeling and virtual screening (29,30). Due to their deacetylase inhibiting properties, the small molecules described above have been suggested to be useful for analysis of the catalytic mechanism of sirtuins and could be antitumor drug candidates (31,32).…”