SALT LAKE CITY, June 14 /PRNewswire/ -- Prolexys Pharmaceuticals and Columbia University announced today a publication describing the properties of the selective small molecule anti-tumor agent, erastin. Prolexys and Columbia applied the company's chemi-proteomics technology to understand the mechanism of action of erastin. The results, to be published in the June 14, 2007 issue of the journal Nature reveal that erastin binds to mitochondrial voltage- dependent anion channels (VDACs) -- a novel target for anti-cancer drugs. Knock-down of VDAC2 and VDAC3 gene expression causes resistance to erastin, implicating the involvement of these two proteins in erastin-mediated cell death. Treatment of cells with erastin results in VDAC-protein-mediated mitochondrial dysfunction, release of oxidative species and, ultimately, cell death. This process has a degree of selectivity for cells with aberrantly active RAS pathway. In normal cells, RAS pathway is involved in growth and differentiation of cells; however the aberrant activation of this pathway results in uncontrolled tumor growth.
Dr. Brent Stockwell, currently an Associate Professor of Biological Sciences and of Chemistry at Columbia University, identified erastin as a small molecule anti-cancer agent that exhibits lethality in human tumor cells with mutations in RAS-related cancer genes such as HRAS, KRAS or BRAF, beginning when he was a Fellow at the Whitehead Institute for Biomedical Research. In February 2005, Prolexys signed an exclusive licensing agreement with the Massachusetts Institute of Technology, as the licensing agent of Columbia University, and the Whitehead Institute, which provides Prolexys with exclusive, worldwide rights to a patent estate covering selective anti-tumor compounds in the erastin family. "This paper demonstrates that it is feasible to discover compounds that produce cancer-cell-selective toxicity and to use these to understand cell death mechanisms in cancer cells; furthermore, the approach revealed a novel cell death pathway," said Dr. Stockwell.
Prolexys launched a medicinal chemistry effort in 2005 to create small molecule analogs of erastin with improved pharmaceutical properties. This effort resulted in the identification of a close structural analog, PRLX 93936, which shows improvement in potency, solubility, and in vivo activity, compared to erastin. PRLX 93936 shows robust and selective toxicity in a wide variety of tumor cell-lines, and causes complete tumor regression in mouse xenograft models of fibrosarcoma, pancreatic cancer, ovarian cancer, colon cancer, and melanoma. Prolexys plans to file an Investigational New Drug (IND) Application for PRLX 93936 with the U.S. Food and Drug Administration (FDA) in June, 2007. Although PRLX 93936 was created as a result of screening hundreds of erastin-related small molecules, its molecular mechanism of action may differ from those of erastin. "Prolexys and collaborators continue to work towards understanding the molecular basis of the unique tumor-selective mechanism of action of erastin and PRLX 93936," said Dr. Sudhir Sahasrabudhe, Chief Scientific Officer of Prolexys Pharmaceuticals.
"The approach described in this paper is a powerful way to identify and test small molecule therapeutics and translate them into the clinic in a time- efficient and cost-efficient manner. We are very excited about evaluating the therapeutic potential of molecules with novel mechanisms of action, such as PRLX 93936 in patients with pancreatic cancer and other solid tumors," said Dr. Daniel Von Hoff, Principal clinical investigator of PRLX 93936, and TGen's Physician-in-Chief and Director of TGen's Clinical Research Service in Scottsdale, Arizona
About Prolexys Pharmaceuticals: Prolexys Pharmaceuticals, Inc. is a privately held biopharmaceutical company focused on discovering small molecule drugs that act on novel therapeutic targets. The Company's therapeutic focus is in cancer and respiratory disease indications where Prolexys has identified novel therapeutic targets and small molecule compounds active at these targets. Prolexys' ability to identify and validate novel targets is driven by its technological leadership in the field of proteomics and the application of proteomics technologies to its own, and its partners, drug discovery programs. For more information about Prolexys, visit the company's website at http://www.prolexys.com.
About Columbia University: A leading academic and research university, Columbia continually seeks to advance the frontiers of knowledge and to foster a campus community deeply engaged in understanding and addressing the complex global issues of our time. Columbia's extensive public service initiatives, cultural collaborations and community partnerships help define the University's underlying values and mission to educate students to be both leading scholars and informed, engaged citizens. Founded in 1754 as King's College, Columbia University in the City of New York is the country's fifth oldest institution of higher learning.
Prolexys Pharmaceuticals, Inc.CONTACT: Dr. Sudhir Sahasrabudhe, CSO of Prolexys Pharmaceuticals,+1-801-303-1714
