Molecular mechanisms of BN108 and timosaponin AIII described in a journal

Bionovo, Inc. (Nasdaq: BNVI) today announced the publication in the peer-reviewed, open-access journal Public Library of Science One (PLoS ONE) of a paper describing the molecular mechanisms underlying the selective cytotoxic activity of its drug candidate BN108 and its active compound, timosaponin AIII.

The mTOR complex regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. The disregulation of the mTOR pathway is implicated as a contributing factor in various cancers which makes mTORC1 an attractive therapeutic target. The endoplasmic reticulum (ER) serves many general functions, including the facilitation of protein folding and the transport of synthesized proteins to the cell membrane. ER stress is elicited by a wide variety of conditions including nutrient deprivation, impaired protein degradation or secretion, calcium imbalance and treatment with some chemotherapeutic drugs. By inhibiting mTORC1 and inducing ER stress BN108 and TAIII activate cell suicide, or apoptosis. Because these drugs do not inhibit mTORC1 and induce little ER stress in normal cells, they selectively kill tumor cells. In addition, BN108 is administered orally, which should increase its utility as an agent that can be given for extended durations for the treatment of various cancers.

"BN108 and timosaponin AIII (TAIII) are cytotoxic towards tumor cells but significantly less to normal cells," said Emma Shtivelman, Ph.D., Director of Cancer Research at Bionovo. "BN108 and TAIII kill tumor cells by eliciting two responses: first, they inhibit the oncogenic pathway known as mTORC1 that is abnormally activated in many tumors. Second, they induce a profound stress in the endoplasmic reticulum of tumor cells. This dual effect of the drug on tumor cells leads to their demise. Normal cells do not have a highly active mTORC1, and TAIII has no effect on the basal activity of this pathway in non-cancerous cells. Therefore, after treatment with the same dose of TAIII or BN108, tumor cells succumb to death, while normal cells survive."

Isaac Cohen, O.M.D., Bionovo's Chairman and CEO, stated: "An important feature of any new anti cancer therapy is the drug's selectivity toward cancer cells, which should result in low toxicity, thus allowing it to be administered for a long duration. BN108 and its active component TAIII, orally administered, have a promising future for treatment of cancer because of their apparent ability to kill cancer cells while sparing normal cells. BN108 and TAIII are part of Bionovo's broad pipeline of novel selective anticancer agents."