A Small-Molecule Inhibitor for Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN)

Abstract

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a phosphoinositide 3-phosphatase, is an important regulator of insulin-dependent signaling. The loss or impairment of PTEN results in an antidiabetic impact, which led to the suggestion that PTEN could be an important target for drugs against type II diabetes. Here we report the design and validation of a small- molecule inhibitor of PTEN. Compared with other cysteine-based phosphatases, PTEN has a much wider active site cleft enabling it to bind the PtdIns(3,4,5)P3 substrate. We have exploited this feature in the design of vanadate scaffolds complexed to a range of different organic ligands, some of which show potent inhibitory activity. A vanadyl complexed to hydroxypicolinic acid was found to be a highly potent and specific inhibitor of PTEN that increases cellular PtdIns(3,4,5)P3 levels, phosphorylation of Akt, and glucose uptake in adipocytes at nanomolar concentrations. The findings presented here demonstrate the applicability of a novel and specific chemical inhibitor against PTEN in research and drug development.

Targeting PTEN using small molecule inhibitors

“…The IC50s for PTP1B is ~20-fold higher and ~13-fold higher for SopB as compared to PTEN. Taken all this observations together, VO-OHpic seems to be the choice of compounds, if PTEN is to be selectively inhibited, which is in agreement with our earlier investigation [11].…”

“…An activation at a concentration of 50 nM can already be detected which is in good agreement with the known in vitro VO-OHpic potency [11,24], demonstrating the good cell permeability of this inhibitor. The fact that 50 nM of VO-OHpic is sufficient to exert cellular effects also means that the chance of hitting other phosphatases can be reduced to a minimum as the determined IC50s for other Cx5R phosphatases is at least 10-fold higher as shown in table 3.…”

“…Bisperoxovanadium compounds were known tyrosine phosphatase inhibitors, which showed a remarkable potency for PTEN in vitro and in vivo [10]. However, these inhibitors are rather promiscuous targeting PTEN in the nanomolar dosage range as well as other phosphatases containing the CX5R active site motif, whereas the 2nd generation PTEN inhibitor VO-OHpic is fairly specific for PTEN in vitro and in vivo [11]. These vanadium-based PTEN inhibitors are currently employed in cellular and animal investigations with some recent applications being listed in Table 1.…”

Metformin and soybean-derived bioactive molecules attenuate the expansion of stem cell-like epithelial subpopulation and confer apoptotic sensitivity in human colon cancer cells

“…HCT116 cells were pre-treated with the PTEN inhibitor SF1670 (2 lM) for 24 h (untreated HCT116 cells served as control); treated cells were subsequently plated under non-adherent conditions with added MET (60 lM), Lun (2 lm), or Gen (2 lM). SF1670 binds to the PTEN active site, resulting in elevated phosphatidylinositol (3,4,5) triphosphate signaling (Rosivatz et al 2006). We found that inhibition of PTEN activity increased colonosphere formation relative to control cells (Fig.…”

Post-translational regulation of PTEN

“…Therefore, enhancing PTEN function by targeting its regulatory machinery can be an effective cancer therapeutic approach. In addition, we suggest that the potential of PTEN targeting in treating other diseases, especially diabetes, should be reconsidered (Kurlawalla-Martinez et al, 2005;Wijesekara et al, 2005;Rosivatz et al, 2006;Sasaoka et al, 2006;Stiles et al, 2006). Previously, the enthusiasm of PTEN inhibition for treating diabetes was dampened because of the undesired tumorigenic effect that might be associated with such treatment.…”