Issue 4, 2022

Structure–activity relationships of hydrophobic alkyl acrylamides as tissue transglutaminase inhibitors

Abstract

Tissue transglutaminase (TG2) is a multifunctional protein that plays biological roles based on its ability to catalyse protein cross-linking and to function as a non-canonical G-protein known as Ghα. The non-regulated activity of TG2 has been implicated in fibrosis, celiac disease and the survival of cancer stem cells, underpinning the therapeutic potential of cell permeable small molecule inhibitors of TG2. In the current study, we designed a small library of inhibitors to explore the importance of a terminal hydrophobic moiety, as well as the length of the tether to the irreversible acrylamide warhead. Subsequent kinetic evaluation using an in vitro activity assay provided values for the kinact and KI parameters for each of these irreversible inhibitors. The resulting structure–activity relationship (SAR) clearly indicated the affinity conferred by dansyl and adamantyl moieties, as well as the efficiency provided by the shortest warhead tether. We also provide the first direct evidence of the capability of these inhibitors to suppress the GTP binding ability of TG2, at least partially. However, it is intriguing to note that the SAR trends observed herein are opposite to those predicted by molecular modelling – namely that longer tether groups should improve binding affinity by allowing for deeper insertion of the hydrophobic moiety into a hydrophobic pocket on the enzyme. This discrepancy leads us to question whether the existing crystallographic structures of TG2 are appropriate for docking non-peptidic inhibitors. In the absence of a more relevant crystallographic structure, the data from rigorous kinetic studies, such as those provided herein, are critically important for the development of future small molecule TG2 inhibitors.

Graphical abstract: Structure–activity relationships of hydrophobic alkyl acrylamides as tissue transglutaminase inhibitors

Supplementary files

Article information

Article type
Research Article
Submitted
02 pro 2021
Accepted
25 sij 2022
First published
26 sij 2022

RSC Med. Chem., 2022,13, 413-428

Structure–activity relationships of hydrophobic alkyl acrylamides as tissue transglutaminase inhibitors

A. M. M. Rangaswamy, P. Navals, E. W. J. Gates, S. Shad, S. K. I. Watt and J. W. Keillor, RSC Med. Chem., 2022, 13, 413 DOI: 10.1039/D1MD00382H

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