Bookmark and Share
BioAssay: AID 652129

Broad Institute MLPCN SirT5 Inhibitor Probe Project

Project Goal: Our goal is to screen the MLPCN collection for compounds that can specifically inhibit Sirt5. These actives will enable the study of posttranslational protein modifications (malonylation/succinylation) in disease states. The potential probe candidates should have the following attributes: ..more
_
   
 Related BioAssays
 Related BioAssays
AID: 652129
Data Source: Broad Institute (7044_Inhibitor_Project)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2013-03-15
Modify Date: 2013-03-21
Related Experiments
AIDNameTypeComment
652115MLPCN SirT-5 Measured in Biochemical System Using Imaging - 7044-01_Inhibitor_SinglePoint_HTS_Activity_Set5Screeningdepositor-specified cross reference: Primary assay
720591MLPCN SirT-5 Measured in Biochemical System Using Imaging - 7044-01_Inhibitor_Dose_CherryPick_Activity_Set5Confirmatorydepositor-specified cross reference
720597MLPCN SirT-5 Measured in Biochemical System Using Imaging - 7044-01_Inhibitor_Dose_CherryPick_Activity_Set6Confirmatorydepositor-specified cross reference
Description:
Primary Collaborators:
Henning Lin,Cornell,Ithaca, NY 14850,H1379@cornell.org
Bin He,Cornell,Ithaca, NY 14850,Hb266@cornell.org

Project Goal: Our goal is to screen the MLPCN collection for compounds that can specifically inhibit Sirt5. These actives will enable the study of posttranslational protein modifications (malonylation/succinylation) in disease states. The potential probe candidates should have the following attributes:

Biological Characteristics:
Target Activity: inhibit Sirt5 desuccinylase activity ##Prior Art: H3K9TSu IC50 5uM Desired Probe: IC50<= 1uM
Selectivity: does not inhibit SirT 1,2,3 deacetylase activity#Prior Art: IC50 > 100 uM Desired Probe: IC50 => 20 uM or 10 fold SirT5 IC50
Biological Mode of Action: Increase succinylated protein in NIH3T3 cells. Desired Probe: Increase 2 fold succinylated protein with active concentration <= 10 uM
Cellular toxicity in panel of mammalian cells (NIH3T3, HEK and HepG2) Desired Probe: IC50> 20 uM or 10 fold the active cellular concentration



Sirtuins, SirT5, lysine malonylation and succinylation, protein posttranslational modifications
Biological Relevance: The Assay Provider's laboratory has recently demonstrated that Sirt5, which has very weak deacetylase activity, can catalyze the hydrolysis of malonyl and succinyl groups from lysine residues (J. Du et al. (2011) SirT5 is an NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806-809). Recently, several malonylated and succinylated proteins were identified from bovine liver mitochondria, demonstrating that lysine malonylation and succinylation are previously unrecognized protein posttranslational modifications (J. Du et al. (2011)). Independently, Zhao and coworkers also demonstrated that protein lysine succinylation and malonylation are new protein posttranslational modifications (2. Z. Zhang, M.Tan, Z.Xie, L.Dai, Y.Chen, Y. Zhao. (2011) Identification of lysine succinylation as a new post translational modification. Nat. Chem. Biol. 7, 58-63). These discoveries raise many interesting questions regarding the role of malonylated and succinylated proteins in disease states. Finding cell permeable Sirt5 selective (over the other 6 human sirtuins) will be extremely helpful for addressing: A.)What is the physiological function of Sirt5-catalyzed demalonylation/desuccinylation? B.) How does malonylation/succinylation regulate protein function? Such inhibitors can be used in cells or model organisms to accumulate malonylated and succinylated proteins. This will facilitate the identification of these posttranslational modified proteins and help study how malonylation/succinylation affects the functions of the proteins. Finding SirT5 selective inhibitors will also provide insights into the biological function of protein malonylation/succinylation. Our goal is to screen for compounds that can specifically inhibit Sirt5.
Categorized Comment - additional comments and annotations
From PubChem:
Assay Cell Type: HEPG2
Additional Information
Grant Number: R21NS073049

PageFrom: