PTEN

Semafore has discovered and is developing small molecule PTEN modulators to selectively up or down regulate PTEN’s phosphatase activity. PTEN (phosphatase and tensin homolog deleted on chromosome 10) is the only known phosphatase controlling PI3K by dephosphorylation of the PIP3 substrate at the 3 position.

Based on cellular signaling mechanisms, activation or temporary inhibition of PTEN by small molecules offer potential therapeutic effects in several disease areas (Figure 1). As shown in Figure 1, activation of PTEN in cells where PTEN is dysfunctional, or where PI3K is over expressed and/or over activated can reestablish the proper cell signaling traffic.

Moreover, inhibition of PTEN can also shift the balance in favor of pro-survival or pro-angiogenesis through activation of AKT and associated downstream signaling elements.

Figure 1. Schematic of PTEN’s Mechanism of Action

Therapeutic Applications

Because of the above signaling relationships, the following therapeutic applications could be possible by the temporary pharmacologic inhibition of PTEN with small molecules.

Cardiovascular Indications - Therapeutic Angiogenesis & Cell Protection:

• Heart Disease Market Overview: Cardiovascular disease (CVD) is a severely unmet medical need. CVD is the second highest cause of death in the US – over one million Americans died from CVD in 2005 alone, and this is second only to cancer.
• PTEN Inhibitor Application in CV/Therapeutic Angiogenesis: Inhibition of PTEN with small molecules has been demonstrated at Semafore to enhance the molecular signaling elements associated with the angiogenic process resulting in increased angiogenesis in certain in vitro angiogenesis models.
• PTEN Inhibitor applications in CVD/Cell Protection (Protecting Cells from Stress-induced Damage): Functional inactivation of PTEN results in constitutive up-regulation of PI3K/Akt signaling which, in turn, promotes cell cycle progression, cellular survival, enhanced protein synthesis, and cell migration. Consequently, a small molecule inhibitor of PTEN could provide short term protection of cells under stress. This has been described in a recent article by an independent group demonstrating the role of PTEN and the therapeutic use of PTEN inhibitors in preventing ischemia (Yellon et al. “PTEN, the Achilles’ heel of myocardial ischaemia/reperfusion injury?” in British Journal of Pharmacology, 2007 p1-6).

Stem Cell Expansion

Market Overview: The interest in the potential use of stem cells therapeutically is extremely high as evidenced by the billions of dollars being allocated by various states such as California for research to expand our knowledge and application of potential stem cell therapies. The current limit to stem cell therapy is the availability of the stem cells for therapy, as they are currently acquired from single donors, and typically the amount of stem cells is too low for therapy.

There are several potential therapeutic applications of stem cell therapy including cardiovascular indications and stem cell transplantation for blood disorders, such as Multiple Myeloma and Non-Hodgkin’s Lymphoma, where stem cell therapy is currently being used to help replenish the bone marrow following therapy.

Stem Cell Transplantation Utility: Stem cell transplantation is a standard medical procedure used to restore the immune system of patients who have had chemotherapy to treat cancers of the immune system such as Multiple Myeloma and Non-Hodgkin's Lymphoma, among others. Approximately 45,000 stem cell transplantations are performed yearly worldwide (IBMTR/ABMTR 2003). Current therapies attempt to increase the number of stem cells available in the patient. Semafore is exploring the use of PTEN inhibitors on stem cells to increase the numbers even more dramatically.