Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase

Abstract

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 exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, 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.

Targeting Tyrosine Phosphatases: Time to End the Stigma

“…Consistent with the above-mentioned role of LMPTP in dephosphorylating the IR, we found that global and liver-specific LMPTP KO protects mice from high-fat diet induced diabetes without affecting body weight[30]. To validate LMPTP as a new type 2 diabetes target, we developed an LMPTP inhibitor[30]. This series was identified by compound screening using a high concentration of OMFP substrate, such that the enzyme was at V max .…”

“…Uncompetitive inhibition occurs when an inhibitor binds to an enzyme-substrate complex[8]. Consistent with the above-mentioned role of LMPTP in dephosphorylating the IR, we found that global and liver-specific LMPTP KO protects mice from high-fat diet induced diabetes without affecting body weight[30]. To validate LMPTP as a new type 2 diabetes target, we developed an LMPTP inhibitor[30].…”

“…Compd. 23 did not cause weight loss in mice and had no effect on diabetes or liver IR tyrosine phosphorylation levels in mice lacking liver-specific expression of LMPTP, confirming the specificity of the inhibitor in vivo and the action of LMPTP in the liver[30]. These findings suggest LMPTP as a key promoter of insulin resistance and that LMPTP inhibitors could have potential for ameliorating type 2 diabetes.…”

“…We recently discovered an orthosteric uncompetitive inhibitor of human LMPTP[30]. Uncompetitive inhibition occurs when an inhibitor binds to an enzyme-substrate complex[8].…”

Targeting Receptor-Type Protein Tyrosine Phosphatases with Biotherapeutics: Is Outside-in Better than Inside-Out?

“…Research over the past decades has established that aberrant PTP signaling, through genetic mutation or altered expression levels, is associated with many human diseases and PTP knock-out mice studies have identified potential therapeutic opportunities for PTP inhibitors (reviewed in [ 11 , 12 , 13 , 14 , 15 ]). The challenges associated with small molecule PTP drug development have been well documented and as yet there are no clinically approved drugs targeting PTPs, although recent notable developments have included the identification of the compound SHP099 [ 16 ], a src homology 2-containing protein-tyrosine-phosphatase (SHP2) inhibitor for treatment of cancers, and low-molecular-weight PTP (LMPTP) inhibitors for diabetes [ 17 ]. Here we provide an update on the emerging area of receptor PTP-targeted biotherapeutics for CD148, VE-PTP, RPTPσ, CD45, RPTPγ, and RPTPζ, and discussion of future potential in this area.…”