Cornell University

The University of Texas System

Biolog Life Science Institute Forshungslabor Und Biochemica-vertrieb Gmbh

Hening Lin

Bin He

Richard A Cerione

Frank Schwede

Bryan A Gibson

W Lee Kraus

Maurine E Linder

Jun Young Hong

A method for determining activity of an acyl transferase enzyme, the method comprising: (i) preparing a reaction mixture comprising: (a) an acyl transferase enzyme, (b) a peptide substrate bound to a fluorophore, wherein the substrate is a cysteine-containing oligopeptide of 5-25 amino acids in length, (c) an acyl-CoA, and (d) a detergent comprising micelles, wherein the acyl transferase enzyme mediates acylation on a cysteine of said peptide substrate to result in association of the peptide with micelles of the detergent with resultant increase in fluorescence polarization; and (ii) measuring fluorescent signal of the reaction mixture; wherein an increase in fluorescence polarization of the reaction mixture compared to fluorescence polarization of a control reaction indicates acyl transferase activity of the acyl transferase enzyme. The above assay method may also be used for screening compounds for their ability to act as inhibitors of an acyl transferase enzyme.

High-throughput enzyme assay for screening activity of acyltransferases

This disclosure demonstrates that inhibition of Sirt5 can suppress malignant transformation of cells. Therefore, methods of treating cancer based on inhibition of Sirt5 are disclosed.

Methods for treatment of cancer by targeting SIRT5

A compound useful as a Sirt2 or Sirt5 inhibitor having the formula (1) wherein: Ris a hydrocarbon group having at least two carbon atoms connected by carbon-carbon bonds, wherein said hydrocarbon group is optionally endcapped by a neutral or anionic oxygen-containing group; R, R, and Rare independently selected from hydrogen atom and hydrocarbon groups; X, X, X, and Xare independently selected from &#x2014;(CH)&#x2014;, &#x2014;NR&#x2014;, &#x2014;O&#x2014;, &#x2014;S&#x2014;, and a bond, wherein n represents 1, 2, or 3, provided that at least one of X-Xis &#x2014;(CH)&#x2014;; and Rand Rare independently selected from the group consisting of hydrogen atom, hydrocarbon groups, biological groups, and protecting groups. Also described are pharmaceutical compositions of the inhibiting compounds, and methods of treatment by administration of the inhibiting compounds. 

Thiourea compounds and their use as inhibitors of Sirt2 or Sirt5

Methods for treatment of cancer by targeting Sirt5

Method for identifying a modulator of Sirt6, PfSir2a, or Sirt7 deacylase activity, wherein a fatty-acylated substrate containing an acyl-lysine moiety and an indicator moiety is contacted with Sirt6, PfSir2a, or Sirt7 in the presence of a candidate compound under conditions for Sirt6, PfSir2a, or Sirt7 to deacylate the substrate, wherein the acyl is a hydrophobic fatty acyl group containing a hydrocarbon group having at least three carbon atoms connected by carbon-carbon bonds; contacting the deacylated substrate with a cleavage agent that cleaves the linkage between the lysine and indicator moiety to generate a detectable signal; and correlating a quantified Sirt6, PfSir2a, or Sirt7 deacylase activity therefrom. Modulating compounds of Sirt6, PfSir2a, or Sirt7 deacylase activity are also described, as are pharmaceutical compositions thereof, methods of treatment by administration of the modulating compounds, and kits for practicing the method.

Modulators for SIRT6 and assays for screening same

Sirt5, a mitochondrial Sirtuin, has been identified herein as an efficient demalonylase and desuccinylase. Disclosed herein are assays to identify Sirt5 modulators based on this robust enzymatic activity. Sirt5-specific modulators can be used study the biological function of Sirt5 and to target Sirt5 activities in treating human diseases.

Modulators for Sirt5 and assays for screening same

The present disclosure provides NAD analogs of the formula: 

NAD analogs and methods of using said NAD analogs in determining ribosylation of proteins with PARP mutants

The instant application describes novel compounds that modulate (in particular, inhibit) Sirt2, with structures according to Formulas (1) and (2) provided herein. The invention is also directed to pharmaceutical compositions thereof, methods of treatment (i.e., cancer and neurodegenerative disease) by administration of the modulating compounds, assay methods for finding modulators of Sirt2, and kits for practicing the assay method.

Methods of treatment using modulators of SIRT2

The instant application describes novel compounds that modulate (in particular, inhibit) Sirt, with structures according to Formulas (1) and (2) provided herein. The invention is also directed to pharmaceutical compositions thereof, methods of treatment (i.e., cancer and neurodegenerative disease) by administration of the modulating compounds, assay methods for finding modulators of Sirt, and kits for practicing the assay method.

Growing community of inventors

Ithaca, NY, United States of America

Hening Lin