Pi-103 – the pik inhibitor

Targeting the PI3K-AKT-mTOR pathway for treatment of various cancers is an effective strategy to reduce tumor cell proliferation, survival and migration. The over-expression of these molecules and the associated pathway has been linked to more than one type of cancers and hence the development of inhibitors targeting this pathway is seen as an efficacious strategy as they can be employed at a wider spectrum. PI-103 PI3K inhibitor is one such molecule that targets the aberrations in this pathway to inhibit PI3K, an action that leads to generate apoptotic response in cancer cells. It has been tested in various cell culture models made up of tumor cells and its efficacy has prompted the researchers and medical practitioners to use it at clinical level.

PHYSICAL PROPERTIES OF PI-103:

PI-103 structure shows that it is a pyridinylfuranopyrimidine molecule. This ATP-competitive inhibitor inhibits various PI3K family members and PI-103 IC50 for effective DNA-PK, p110α, mTORC1, PI3-KC2β, p110δ, mTORC2, p110β, and p110γ inhibition is 2 nM, 8 nM, 20 nM, 26 nM, 48 nM, 83 nM, 88 nM and 150 nM, respectively. Against other kinases though, it shows no specificity. PI-103 price is on the higher side only and one can buy PI-103's 10 mg vial for around $150 from any PI-103 supplier. PI-103 solubility can be achieved in DMSO to give a 100 mM solution. PI-103 stability can be gained by storing it at +4°C after desiccation.

PHARMACOLOGICAL ASSESSMENT OF PI-103:

In difficult to treat glioma cells, PI-103 was shown to induce proliferative arrests by inhibiting both PI3Ka and mTOR. In tumor xenografts derived from malignant glioma cells, there was no toxicity reported upon PI-103 treatment [1]. PI-103 is metabolized extensively, but is distributed rapidly to tumor cells resulting in tumor growth delay in human tumor xenografts carrying PI3K pathway aberrations. PI-103 shows decreased angiogenesis in glioma cells and ovarian and breast cancer xenografts [2]. In leukemic cell lines derived from humans and in primary blast cells from acute myeloid leukemia (R406) patients, PI-103 was shown to inhibit growth factor-induced and/or constitutive mTORC1 and PI3K/Akt activation and it induced cell cycle arrest and mitochondrial apoptosis in these models [3].

PI-103 showed synergistic apoptotic effects when given with Etoposide to blast immature leukemic cells, sparing normal CD34 +ve cells [3]. In Gefitinib treatment-resistant non-small cell lung cancer (NSCLC) cells, PI-103 treatment induced apoptosis by inhibiting p70S6K and Akt phosphorylation. PI-103 downregulated cyclin D1 and E1 and activated p21, p53 and p27 to lead to a G0-G1 arrest. [4]. Its combination with Doxorubicin reduced colony formation and increased apoptosis drastically in comparison to chemotherapy alone and the underlying mechanism was shown as its inhibition of PI3K, DNA-PK and mTOR and concurrent doxorubicin-induced DNA damage to contribute to apoptosis in glioma cell lines and stem cells [5]. The DNA damage coupled with prolonged Rad 51 and γH2AX foci after PI-103 treatment contributes to G2-M delay [6]. It shows synergistic effects with Nutlin-3 also by inducing conformational changes in Bax and caspase-3 activation to dephosphorylate 4E-BP1 leading to decreased Mdm2, Noxa, p21, survivin and Bcl-2 expression [7]. In in vitro and in vivo glioma mouse models, a reduced proliferation and invasion coupled with G0–G1 arrest is seen upon PI-103's co-treatment with secretable tumor necrosis factor apoptosis-inducing ligand (Perifosine) [8]. It kills non-APL leukemia cells in combination with Arsenic disulfide sparing normal hematopoietic stem cells [9]. Similarly it showed potent synergistic effects with TCN in Trp53 and Nf1 mutation carrying astrocytoma cells [10]. The success of these preclinical trials calls for PI-103 clinical trial.

REFERENCES:

1.             Fan QW, e.a., A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell, 2006.

2.             Raynaud FI, e.a., Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res., 2007.

3.             Park S, e.a., PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia, 2008.

4.             Zou ZQ, e.a., A novel dual PI3Kα/mTOR inhibitor PI-103 with high antitumor activity in non-small cell lung cancer cells. International Journal of Molecular Medicine, 2009.

5.             Westhoff MA, e.a., The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repairChemosensitization of glioblastoma by PI-103. Oncogene, 2009.

6.             Prevo R, e.a., Class I PI3 Kinase Inhibition by the Pyridinylfuranopyrimidine Inhibitor PI-103 Enhances Tumor Radiosensitivity. Cancer Res., 2008.

7.             Kojima K, e.a., The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AMLPI-103 effects in p53 wild-type AML. Leukemia, 2008.

8.             Onder TB, e.a., A Dual PI3K/mTOR Inhibitor, PI-103, Cooperates with Stem Cell-Delivered TRAIL in Experimental Glioma Models. Cancer Res., 2011.

9.             Hong Z, e.a., Arsenic disulfide synergizes with the phosphoinositide 3-kinase inhibitor PI-103 to eradicate acute myeloid leukemia stem cells by inducing differentiation Carcinogenesis, 2011.

10.          Gürsel DB, e.a., Control of proliferation in astrocytoma cells by the receptor tyrosine kinase/PI3K/AKT signaling axis and the use of PI-103 and TCN as potential anti-astrocytoma therapies. Neuro Oncol, 2011.

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