mitochondrial inhibitors

Our lead candidates within this program display a novel mechanism of action, targeting a mitochondrial component of the terminal respiratory chain complex in rapidly proliferating cells. Treatment of tumor cells with our mitochondrial inhibitor compounds induces a rapid loss of cellular energy and leads to the inhibition of both mammalian target of rapamycin (mTOR1 and mTOR2) pathways.

first generation: NV-128

The majority of studies conducted thus far have been on a compound called NV-128. Pre-clinical studies have demonstrated that NV-128 induces caspase-independent cell death by way of both DNA fragmentation and destructive autophagy.

The mechanism of action results in a rapid loss of cellular ATP and a concomitant increase in ADP and AMP, ultimately leading to the dephosphorylation of the mammalian target of rapamycin (mTOR) and the disassembly of both the mTOR1 and mTOR2 pathways.

NV-128 has shown activity in pre-clinical models against a broad range of cancers, including KRAS-mutant, Tarceva-resistant non-small cell lung cancer cell lines.

Of particular interest are results from an ongoing study conducted in collaboration with Dr. Gil Mor, a gynecological oncologist at the Yale School of Medicine, which demonstrate that NV-128 is uniformly active against all chemotherapy-resistant ovarian tumor cells tested to date.

next generation: ME-344

We have identified an active metabolite of NV-128 in a compound we call ME-344. In pre-clinical studies, ME-344 has shown tenfold more anti-tumor activity than NV-128. We have completed the necessary pre-clinical animal toxicity studies and submitted an Investigational New Drug (IND) application in March 2012. We plan to initiate a Phase I clinical trial of intravenous ME-344 in patients with solid refractory tumors following approval of our IND by the U.S. Food & Drug Administration (FDA).