4 research outputs found
Structure–Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase
Human tissue transglutaminase (hTG2)
is a multifunctional enzyme.
It is primarily known for its calcium-dependent transamidation activity
that leads to formation of an isopeptide bond between glutamine and
lysine residues found on the surface of proteins, but it is also a
GTP binding protein. Overexpression and unregulated hTG2 activity
have been associated with numerous human diseases, including cancer
stem cell survival and metastatic phenotype. Herein, we present a
series of targeted covalent inhibitors (TCIs) based on our previously
reported Cbz-Lys scaffold. From this structure–activity relationship
(SAR) study, novel irreversible inhibitors were identified that block
the transamidation activity of hTG2 and allosterically abolish its
GTP binding ability with a high degree of selectivity and efficiency
(<i>k</i><sub>inact</sub>/<i>K</i><sub>I</sub> > 10<sup>5</sup> M<sup>–1</sup> min<sup>–1</sup>).
One optimized inhibitor (<b>VA4</b>) was also shown to inhibit
epidermal cancer stem cell invasion with an EC<sub>50</sub> of 3.9
μM, representing a significant improvement over our previously
reported “hit” <b>NC9</b>
Structure–Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase
Human tissue transglutaminase (hTG2)
is a multifunctional enzyme.
It is primarily known for its calcium-dependent transamidation activity
that leads to formation of an isopeptide bond between glutamine and
lysine residues found on the surface of proteins, but it is also a
GTP binding protein. Overexpression and unregulated hTG2 activity
have been associated with numerous human diseases, including cancer
stem cell survival and metastatic phenotype. Herein, we present a
series of targeted covalent inhibitors (TCIs) based on our previously
reported Cbz-Lys scaffold. From this structure–activity relationship
(SAR) study, novel irreversible inhibitors were identified that block
the transamidation activity of hTG2 and allosterically abolish its
GTP binding ability with a high degree of selectivity and efficiency
(<i>k</i><sub>inact</sub>/<i>K</i><sub>I</sub> > 10<sup>5</sup> M<sup>–1</sup> min<sup>–1</sup>).
One optimized inhibitor (<b>VA4</b>) was also shown to inhibit
epidermal cancer stem cell invasion with an EC<sub>50</sub> of 3.9
μM, representing a significant improvement over our previously
reported “hit” <b>NC9</b>
Structure–Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase
Human tissue transglutaminase (hTG2)
is a multifunctional enzyme.
It is primarily known for its calcium-dependent transamidation activity
that leads to formation of an isopeptide bond between glutamine and
lysine residues found on the surface of proteins, but it is also a
GTP binding protein. Overexpression and unregulated hTG2 activity
have been associated with numerous human diseases, including cancer
stem cell survival and metastatic phenotype. Herein, we present a
series of targeted covalent inhibitors (TCIs) based on our previously
reported Cbz-Lys scaffold. From this structure–activity relationship
(SAR) study, novel irreversible inhibitors were identified that block
the transamidation activity of hTG2 and allosterically abolish its
GTP binding ability with a high degree of selectivity and efficiency
(<i>k</i><sub>inact</sub>/<i>K</i><sub>I</sub> > 10<sup>5</sup> M<sup>–1</sup> min<sup>–1</sup>).
One optimized inhibitor (<b>VA4</b>) was also shown to inhibit
epidermal cancer stem cell invasion with an EC<sub>50</sub> of 3.9
μM, representing a significant improvement over our previously
reported “hit” <b>NC9</b>
Unraveling the Prenylation–Cancer Paradox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate Synthase (GGPPS) Inhibitors
Post-translational prenylation of
the small GTP-binding proteins
(GTPases) is vital to a plethora of biological processes, including
cellular proliferation. We have identified a new class of thienopyrimidine-based
bisphosphonate (ThP-BP) inhibitors of the human geranylgeranyl pyrophosphate
synthase (hGGPPS) that block protein prenylation in multiple myeloma
(MM) cells leading to cellular apoptosis. These inhibitors are also
effective in blocking the proliferation of other types of cancer cells.
We confirmed intracellular target engagement, demonstrated the mechanism
of action leading to apoptosis, and determined a direct correlation
between apoptosis and intracellular inhibition of hGGPPS. Administration
of a ThP-BP inhibitor to a MM mouse model confirmed in vivo downregulation
of Rap1A geranylgeranylation and reduction of monoclonal immunoglobulins
(M-protein, a biomarker of disease burden) in the serum. These results
provide the first proof-of-principle that hGGPPS is a valuable therapeutic
target in oncology and more specifically for the treatment of multiple
myeloma