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. 2013 Aug 1;23(15):4408-12.
doi: 10.1016/j.bmcl.2013.05.069. Epub 2013 May 30.

Phosphinic acid-based inhibitors of tubulin polyglutamylases

Yanjie Liu  1 , Christopher P Garnham, Antonina Roll-Mecak, Martin E Tanner
Affiliations

Phosphinic acid-based inhibitors of tubulin polyglutamylases

Yanjie Liu et al. Bioorg Med Chem Lett. .

Abstract

Tubulin is subject to a reversible post-translational modification involving polyglutamylation and deglutamylation of glutamate residues in its C-terminal tail. This process plays key roles in regulating the function of microtubule associated proteins, neuronal development, and metastatic progression. This study describes the synthesis and testing of three phosphinic acid-based inhibitors that have been designed to inhibit both the glutamylating and deglutamylating enzymes. The compounds were tested against the polyglutamylase TTLL7 using tail peptides as substrates (100 μM) and the most potent inhibitor displayed an IC₅₀ value of 150 μM. The incorporation of these compounds into tubulin C-terminal tail peptides may lead to more potent TTLL inhibitors.

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Figures

Figure 1
Figure 1
The initiation and elongation steps of tubulin polyglutamylation catalyzed by the TTLL enzymes.
Figure 2
Figure 2
A. The mechanism employed by the ATP-dependent amino acid ligases. B. The structure of phosphinic acid-based inhibitors and the potential phosphorylation of the inhibitor within the ligase active site.
Figure 3
Figure 3
The structure of the potential intermediates involved in tubulin polyglutamylation and the corresponding inhibitors targeted against them.
Figure 4
Figure 4
A plot of normalized activity versus the concentration of inhibitor 2 (log plot) for the inhibition of tubulin C-terminal peptide (100 µM) glutamylation by TTLL7.
Scheme 1
Scheme 1
Scheme 2
Scheme 2
See this image and copyright information in PMC

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