Nature has bestowed many health benefits on the green tea flavonoid, (-) epigallocatechin-3-gallate (EGCG). EGCG has been demonstrated to inhibit tumor growth and development in numerous animal models. It has been shown to inhibit cell proliferation, induce apoptosis, and inhibit angiogenesis, invasion, and tumor cell migration.

Various potential mechanisms contributing to the antitumor effects of EGCG have been described, however, many of these studies used non-physiological concentrations of EGCG and many of the noted effects are indirect. We were the first to elucidate inhibition of the chymotrypsin-like activity of the proteasome as a primary molecular target of EGCG. This can contribute to diverse downstream effects. We also feel that inhibition of PI3K/Akt/mTOR signalling is an important secondary pathway affected by EGCG, distinguishing its mechanism of action from other proteasome inhibitors. Inhibition of these two pathways can result in unique synergies not seen with other compounds.

Nature has designed EGCG to affect several cellular signalling pathways with an appropriate balance to achieve its biological effects without significant toxicity. Accordingly, EGCG has been demonstrated to inhibit the growth of tumor cells without affecting their normal counterparts.

However, a major challenge in extrapolating the biological activities of EGCG to improved clinical benefits, is its bioavailability. Viteava’s innovative candidate drugs are modifications of the EGCG chemical structure resulting in improved bioavailability and enhanced antitumor activity.

VPE001 is a prodrug of EGCG with improved potency and bioavailability. It has demonstrated antitumor activity in mouse xenograft models of human estrogen receptor-negative breast cancer, and human androgen-independent prostate cancer. It has also been demonstrated to markedly reduce the development of colon cancer in a dextran sulfate sodium- and azoxymethane-induced mouse model. Similarly, VPE001 has been shown to reduce tumor incidence and multiplicity in a DMBA-initiated and TPA-promoted mouse skin cancer model. Recently, VPE001 has demonstrated potent anti-angiogenic effects in a mouse model of endometriosis. VPE001 inhibits the growth of leiomyoma cell lines in vitro and in vivo. VPE001 is poised to enter IND-enabling preclinical development.

VPEA002 & VPEA004 are analogs of VPE001, with increased proteasome-inhibitory, pro-apoptotic and anti-proliferative potency. The company is currently assessing the oral bioavailability and pharmacokinetics of these compounds prior to further characterization in animal models.

VEA005 & VEA006 are EGCG analogs identified as potent AMP-activated protein kinase (AMPK) activators that synergize with bortezomib, docetaxel and erlotinib. VEA005 and VEA006 have been demonstrated to inhibit proliferation of human breast cancer cells in a dose-dependent fashion, while also activating AMPK, Raptor and p21 in a dose-dependent fashion, and demonstrating increased potency over both EGCG and metformin. They also target cancer stem or stem-like cells and inhibit mammosphere formation in a dose-dependent fashion, again being more potent than EGCG and metformin.