Targeting PTEN using small molecule inhibitors

Abstract

PTEN (phosphatase and tensin homologue deleted on chromosome 10) is well known as a tumour suppressor. It's PI(3,4,5)P 3 lipid phosphatase activity is an important counteracting mechanism in PI3K (phosphoinositide 3-kinase) signalling. Furthermore, PTEN lies upstream of Akt kinase, a key enzyme in insulin signalling regulating glucose uptake and cell growth. Therefore, PTEN has recently gained attention as a valuable drug target for the treatment of diabetes, stroke, cardiac infarct and fertility. This review summarizes the use of small molecules as PTEN inhibitors. Currently available methodologies and techniques for accessing PTEN inhibition in vitro and in cellulo will be discussed. Keywords: PTEN, inhibition, Vanadium compounds, OMFP, VO-OHpic IntroductionThe phosphatidylinositol (PI) 3-phosphatase PTEN has been initially characterised as tumour suppressor gene with a putative tyrosine phosphatase domain [1], but has since then proven to be a dual specificity phosphatase having inositol lipids as substrates [2]. PTEN is dephosphorylating 3-phosphorylated inositol lipids, counteracting the action of PI3 kinases by removing the "second messengers" created by the action of growth factors, cytokines and cell survival stimulators [2][3][4]. Chemical intervention tools, such as wortmannin [5], LY294002 [6] or theophylline [7] facilitated the discovery of new chemical inhibitors, with all chemical intervention tools having a tremendous impact on the elucidation of the role of PI 3-kinases in disease and cancer development [8,9]. PTEN was discovered much later than the PI 3-kinases, and the first PTEN inhibitors were developed in due course a decade ago exploiting the dual specificity nature of the PTEN phosphatase. 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

Targeting chondroitinase ABC to axons enhances the ability of chondroitinase to promote neurite outgrowth and sprouting

“…A similar increase in neurite length was produced by the PTEN inhibitor VO-OHpic [25]. This is a vanadium-based potent inhibitor of PTEN which, unlike some of the other vanadium based inhibitors, is highly specific for PTEN [35]. VO-OHpic had no effect on PTEN mRNA levels, suggesting that blocking PTEN function doesn't result in any feedback loop to PTEN transcription.…”

Phosphatidylinositol 3‐phosphates—at the interface between cell signalling and membrane traffic

“…• Inhibitors of the PI(3,4,5)P 3 3-phosphatase PTEN (e.g. SF1670, bpV (phen), bpV(pic), or VO-OHpic) have been reported and shown to cause elevated PI(3,4,5)P 3 levels and overactivation of the Akt pathway with corresponding effects on cell polarization, migration, akin to genetic PTEN loss-of-function models (Di Cristofano et al, 1998;Song et al, 2012;Mak & Woscholski, 2015), however that may inhibit other enzymes such as the PI 4-phosphatases INPP4A/B (Spinelli et al, 2015). (Miura et al, 2000;Itoh et al, 2002), the cytokinesis factor FYVE-CENT (Sagona et al, 2010), the PI(3)P phosphatase MTMR4 (Lorenzo et al, 2006;Naughtin et al, 2010), ALFY (autophagy-linked FYVE protein), a protein that targets ubiquitincontaining protein aggregates for autophagic degradation (Simonsen et al, 2004) and the omegasome protein DFCP1 (double FYVE containing protein 1) (Polson et al, 2010).…”

Vanadium: History, chemistry, interactions with α-amino acids and potential therapeutic applications

“…Only some oxovanadium(IV) complexes have shown an inhibitory effect on SHP-1, suggesting that these compounds, such as Na 2 [VO(Glu) 2 (CH 3 OH)] and 2-((5-Nitro-2-oxybenzylidene)amino) benzoato-diaqua-oxovanadium(IV), play an important role in enzyme selectivity [168,171]. The bisperoxovanadium compounds has been described as inhibitor of PTEN (phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase) [172,173], another important counter-regulator of insulin signaling [173,174]. However, inhibition by vanadium complexes with amino acids has not been demonstrated.…”