Potential new therapies for cancer and bleeding disorders

Lexicon Genetics announced today that it has advanced two of its drug discovery programs into preclinical development in preparation for investigational new drug (IND) applications.

The first, LX-1521, is a small molecule compound to be developed as a potential cancer treatment. The second, LX-5431, is a protein to be developed as a potential biotherapeutic for thrombocytopenia, a condition that results in bleeding disorders. The functions of the targets of both potential therapies were discovered in Lexicon's Genome5000 gene knockout program. This program has produced more than 60 drug discovery programs to date.

LX-1521 is a novel small molecule compound with potential for treating solid tumor cancers. LX-1521 works by blocking the cell cycle prior to cell division, resulting in cancer cell death through apoptosis. When administered orally to mouse models of human cancer, LX-1521 demonstrates significant anti- tumor activity in vivo while exhibiting no apparent gross toxicity. In vitro, the compound inhibits growth of more than 20 human tumor cell lines derived from multiple types of cancer. Potential uses of LX-1521 as a cancer therapy include the treatment of breast, prostate, lung, colon, ovarian, renal and pancreatic cancer, as well as melanoma.

LX-1521 was discovered in Lexicon's LG152 kinase target program. Lexicon found that this kinase plays a role in cell proliferation when cells from knockout mice lacking the LG152 gene exhibited a decreased rate of growth. Lexicon then demonstrated that cells overexpressing LG152 form tumors in nude mice, indicating that LG152 can function as an oncogene. LX-1521 is one of a number of potent inhibitors of LG152 created in Lexicon's medicinal chemistry program. The mechanism of action of LX-1521 likely also includes inhibition of other kinase targets, a characteristic of many small molecule kinase inhibitors. Lexicon expects to file an IND for LX-1521 by the end of 2005 and commence a Phase 1 clinical trial for the compound shortly thereafter.

"Our preclinical research to date indicates that LX-1521 effectively inhibits tumor growth in animal models without the toxicity typical of many current chemotherapy drugs," said Arthur T. Sands, M.D., Ph.D., president and chief executive officer of Lexicon. "Based on our current understanding of LX-1521's mechanism of action, we believe it has potential as a targeted therapy for cancer."

All cancers involve the malfunction of genes that control cell growth and division. According to the American Cancer Society, approximately one out of every two American men and one out of every three American women will have some type of cancer at some point during their lifetime. This year, more than 500,000 Americans are expected to die of cancer and more than 1.3 million new cancer cases are expected to be diagnosed in the United States. Prostate cancer is the most prevalent cancer in men, representing 33% of new cancer cases. In women, breast cancer is most prevalent, representing 32% of new cancer diagnoses.

LX-5431 is a novel recombinant human protein with the potential for treating thrombocytopenia, a disorder characterized by a lack of platelets in the blood that can lead to severe bleeding. LX-5431 has been demonstrated in ex vivo bone marrow culture to stimulate production of platelet forming cells called megakaryocytes. LX-5431 may have potential for treating thrombocytopenia resulting from chemotherapy, leukemia, autoimmune disease and other conditions.

LX-5431 was identified in Lexicon's LG543 secreted protein program. Lexicon discovered that this secreted protein is a growth factor required for platelet production when the LG543 gene knockout was observed to have decreased platelet concentration in the blood. The LG543 gene knockout also exhibited a decreased percentage of megakaryocytes in the bone marrow and spleen. Lexicon's scientists cloned the human gene and produced the recombinant human protein. During 2005, Lexicon expects to develop scale-up methodologies to produce LX-5431 in quantities required for preclinical and early clinical development.

Thrombocytopenia can result from a variety of conditions including exposure to chemotherapeutic agents, leukemia, bone marrow transplantion and autoimmune disease. Chemotherapy, in particular, can greatly reduce platelet levels, and chemotherapy patients often require blood transfusions to protect against excessive bleeding. Each year in the United States, approximately eight million units of platelets are transfused into patients to reduce the risk of severe bleeding (New England Journal of Medicine, March 1998, pages 746-754).

"Discovery of a drug to increase platelet production has been a long standing objective of the biopharmaceutical industry," said Brian P. Zambrowicz, Ph.D., executive vice president of research at Lexicon. "Our data suggest that LX-5431 offers promise in meeting this major medical goal."

The LG152 and LG543 drug targets were discovered in Lexicon's Genome5000 program. In this program, Lexicon is using its proprietary gene knockout technology to rapidly discover the physiological and behavioral functions of 5,000 of the most pharmaceutically important genes in the human genome. To date, Lexicon has completed the analysis of more than 2,000 of these genes and has harvested more than 60 drug discovery programs. In addition to cancer and immune systems disorders, Lexicon has drug discovery programs in the fields of diabetes and obesity, cardiovascular disease, ophthalmic disease and psychiatric and neurological disorders.