29 research outputs found
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Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase.
Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, and it increases liver IR phosphorylation in vivo and reverses high-fat diet-induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes
Recommended from our members
Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase.
Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, and it increases liver IR phosphorylation in vivo and reverses high-fat diet-induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes
Characterization of Potent SMAC Mimetics that Sensitize Cancer Cells to TNF Family-Induced Apoptosis - Fig 4
<p>Condensed structures (A,B, and C) of the compounds series described in Tables <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161952#pone.0161952.t001" target="_blank">1</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161952#pone.0161952.t002" target="_blank">2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161952#pone.0161952.t003" target="_blank">3</a>. (D) Structure of P<sub>2</sub> substituent of compound <b>18</b>.</p
Expedient Synthesis of Highly Potent Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Unique Selectivity for ML-IAP
A series of novel, potent antagonists of the inhibitor
of apoptosis
proteins (IAPs) were synthesized in a highly convergent and rapid
fashion (≤6 steps) using the Ugi four-component reaction as
the key step, thus enabling rapid optimization of binding potency.
These IAP antagonists compete with caspases 3, 7, and 9 for inhibition
by X chromosome-linked IAP (XIAP) and bind strongly (nanomolar binding
constants) to several crucial members of the IAP family of cancer
pro-survival proteins to promote apoptosis, with a particularly unique
selectivity for melanoma IAP (ML-IAP). Experiments in cell culture
revealed powerful cancer cell growth inhibitory activity in multiple
(breast, ovarian, and prostate) cell lines with single agent toxicity
at low nanomolar levels against SKOV-3 human ovarian carcinoma cells.
Administration of the compounds to human foreskin fibroblast cells
revealed no general toxicity to normal cells. Furthermore, computational
modeling was performed, revealing key contacts between the IAP proteins
and antagonists, suggesting a structural basis for the observed potency
Correlation between K<sub>i</sub> of the cIAP BIR domains and their EC<sub>50</sub>.
<p>Log of the K<sub>i</sub> values for SMAC peptide displacement as measured by FPA was plotted against cell viability EC<sub>50</sub> values using the data shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161952#pone.0161952.g005" target="_blank">Fig 5</a> for either TNF or LT-α. Correlations coefficient (r) and p-values are indicated.</p
Binding affinities of hydrazine series SMAC mimetic compounds for BIR domains of cIAP1 and cIAP2<sup>a</sup>.
<p>Binding affinities of hydrazine series SMAC mimetic compounds for BIR domains of cIAP1 and cIAP2<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161952#t003fn002" target="_blank"><sup>a</sup></a>.</p
Competition of SMAC-7-mer with SMAC-rhodamine.
<p>Assays conditions were 25 mM Hepes @ pH 7.5, 1 mM TCEP, 0.005% Tween 20 and 20 nM SMAC-rhodamine. Where cIAP1-BIR3 was present, 40 mM β-glycerol phosphate was also present in the assay. Proteins were present at ~50 nM for cIAP1-BIR3, 125 nM for cIAP2-BIR3, and at 1 μM for both cIAP1-BIR2 and cIAP2-BIR2. SMAC peptide (AVPIAQK) ranged between ~6 nM and 100 μM.</p