The drug-like potential of TG53 is supported by its predicted physico-chemical properties computed based on its chemical structure by using the ADMET Predictor and ChemSpider software. It is encouraging that TG53 is predicted to be orally bioavailable, violates none of the Lipinski’s rule of five, and passes the Muegge filter, suggesting that it can serve as a suitable basis for the development of drug like agents. The LogP value of TG53 was 4.5; well within the range of most SMIs approved for clinical use and its aqueous solubility was low at 5.45 mole/liter. Its predicted cellular permeability in Madin-Darby canine kidney cells was 378, the highest among the top hits selected from the screen, indicating intermediate solubility. Further optimization of this compound may increase its potency, cellular permeability, and bioavailability. As the TG2-FN interaction plays a role in cell adhesion to the matrix, we postulate that SMIs targeting this complex may be developed into agents that block cancer metastasis, particularly for tumors like ovarian cancer that rely on adhesion to the ECM, as a primary mode of dissemination. We recognize 
that SMIs targeting the TG2-FN interaction might interfere with other physiological processes mediated by this PPI, such as formation of blood clots, wound healing, or certain immune responses involving cell adhesion to FN. Therefore, future evaluation of such SMI in vivo must include careful assessment of potential toxic effects due to interference with TG2-mediated physiologic processes. In summary, our results support that the TG2-FN interaction is a novel targetable PPI whose disruption could inhibit cell adhesion to the ECM. The AlphaLISATM NSC 136476 500579-04-4 technology based assay developed here is suitable for HTS and can be used to screen larger libraries. We propose that the top compound identified, TG53, is a specific inhibitor of the TG2-FN complex with potential utility as a novel therapeutic targeting cancer metastasis or as a new biochemical tool to study cell adhesion to the matrix. In order to maintain rapid proliferation and survival, cancer cells depend on high rates of MDV3100 protein synthesis and on selective translation of cap-dependent mRNAs encoding cell cycle regulators and anti-apoptotic proteins. Eukaryotic initiation factor 4E, which together with eukaryotic initiation factor 4G and eukaryotic initiation factor 4A form the capbinding complex, is frequently overexpressed in human cancer and can cooperate with the Myc oncogene in an experimental lymphoma model. Consequently, drugs targeting eIF4E and other translation factors have received increased attention as possible therapeutic approaches in leukemia and lymphoma. A key upstream regulator of eIF4E is the serine/threonine kinase mTOR. Elevated mTOR activity is a prominent feature of cancer cells, including hematological malignancies. The mTOR enzyme forms two complexes, TORC1 and TORC2, which are independently regulated and have distinct substrates. One set of important TORC1 substrates are the eIF4E-binding proteins, 4EBP1 and 4EBP2. When dephosphorylated, these proteins suppress cap-dependent translation by sequestering eIF4E. TORC1 phosphorylates 4EBPs to relieve eIF4E inhibition and promote cap-dependent translation. The classical mTOR inhibitor rapamycin functions through an allosteric mechanism. Rapamycin or its analogs form an intracellular gain-of-function complex with FK506 binding protein 12 that disrupts the stability of TORC1 and reduces phosphorylation of certain substrates. Rapalogs inhibit phosphorylation of S6 kinase very efficiently, but have lesser impact on the phosphorylation of 4EBP1 and 4EBP2 by TORC1. Active-site mTOR inhibitors are a novel class of anticancer drugs that suppress both rapamycin-sensitive and rapamycin-resistant functions of TORC1 and TORC2.