Anti-cancer agent mechanism for high activity and low neurotoxicity published by McGill researchers

November 24, 2016

Diazon Pharmaceuticals Inc. last week announced the publication of a preclinical oncology study identifying the novel mechanism of action of its new synthetic diazonamide compound, DZ-2384, in Science Translational Medicine. The results show that a distinct mode of binding to a classic therapeutic site in tubulin translates into superior anti-tumor activity and safety, including lack of neurotoxicity, with pre-clinical proof of concept in a wide range of cancers including triple-negative breast cancer and pancreatic cancer.

The study, titled “The synthetic diazonamide DZ-2384 has distinct effects on microtubule curvature and dynamics without neurotoxicity,” by Michal Wieczorek et al., highlights distinct structural features of DZ-2384 binding to tubulin that help preserve the cell microtubular infrastructure of neurons and non-dividing cells, resulting in lower toxicity. DZ-2384’s novel mechanism of action was shown to result in unique effects on microtubule curvature and dynamics distinct from other agents in its class.

Anti-mitotic tubulin-binding agents constitute part of the standard-of-care in over 15 different oncology indications. Treatment is accompanied by significant toxicities including neurotoxicity that often limit their use and effectiveness. In contrast, DZ-2384 did not cause peripheral neuropathy at efficacious doses, yet retained potent activity in preclinical models.

Diazon partnered with the Laboratory for Therapeutic Development at the Rosalind and Morris Goodman Cancer Research Center, McGill University to elucidate DZ-2384’s mechanism of action and to determine which cancers are likely to derive the most therapeutic benefit from this agent. The research was led by Drs. Anne Roulston and Gordon Shore of the Laboratory for Therapeutic Development and Dr. Gary Brouhard at the University’s Department of Biology and included several international collaborators.

Robert G. McNeil, Ph.D., chairman of the board of directors of Diazon, said “Anti-mitotic agents represent the bedrock standard-of-care for thousands of cancer patients worldwide. Their narrow safety margin, including high incidences of peripheral neuropathy, severely restrict their utility. The positive results of both drug efficacy and toxicity studies leads us to believe that DZ-2384 has a wide safety margin with the potential to treat a substantial patient population across multiple cancer indications. The publication in this prestigious journal emphasizes the importance and timeliness of DZ-2384 in an era of intense interest in safely combining chemotherapy with targeted agents. The findings reinforce our expectations that DZ-2384 will present a significant improvement in the treatment of multiple cancers.”
Anne Roulston, Ph.D., associate director of the Laboratory for Therapeutic Development at the Goodman Cancer Research Center, McGill University, said “The data provide us with key insights into the basic attributes of DZ-2384 and demonstrate preclinical proof of its validity as a new generation of chemotherapy. Such a drug could be used both as sole treatment or in combination with other therapies, such as immuno-oncology. We believe DZ-2384 has the potential to be a highly effective and safer alternative to current anti-mitotic agents.”

November 24, 2016