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Oral Pan-Bcl-2 Inhibitors
(CNDO103 [apogossypol]—second generation); 8r—third generation)

Cancer: Trapping the Escape Artist.   Researchers deliver a better understanding of anti-cell death proteins and a potential antagonist to defeat them From the Sanford/Burnham Institute of Medical Research,  LA JOLLA, Calif., May 11, 2010

Tumor expression in disease types.

Background
The Bcl-2 family of proteins control programmed cell death, or apoptosis. All cell types undergo apoptosis as part of normal growth and development. This complex yet elegant system includes 5 death proteins that trigger apoptosis (BAK, BIM. BAX, BID, PUMA.) These death proteins are held in check by 6 pro-survival proteins (Bcl-2, Bcl-xl, Mcl-1, Bcl-B, Bcl-W and Bfl-1.) The balance, or ratio, between the death proteins and pro-survival proteins is critical. One consequence of an abnormal ratio is the uncontrolled cell growth common to cancer. For a detailed schematic of apoptosis, please click here.

In many cancer types, over-expression (elevated production) of the Bcl-2 pro-survival protein results in abnormal cell growth with reduced capability for apoptosis and resistance to standard cancer therapy. Bcl-2 inhibitors inactivate the Bcl-2 pro-survival proteins that perpetuate this dysfunction and return the balance of death proteins to pro-survival proteins to normal. In turn, apoptosis resumes as usual, preventing tumor growth, and cancer cells once again become sensitive to chemotherapy and radiation therapy.

The majority of cancer tumor types possess elevated Bcl-2 family proteins; prostate, breast, colorectal cancer, non-Hodgkin lymphoma (NHL), and leukemia are all largely characterized by over-expression of one or more of the Bcl-2 pro-survival proteins. Consequently, Bcl-2 inhibitors can be used as part of the treatment for many different cancer types.

Application
In general, the more pro-survival proteins a drug inhibits, the greater its therapeutic value. The initial Coronado Biosciences oral pan-Bcl-2 inhibitor, apogossypol (CNDO103), is a second-generation derivative of the gossypol compound. CNDO103 targets 5 of the 6 pro-survival Bcl-2 proteins, effectively triggering apoptosis of cancer cells in the blood and solid tumors and delaying the growth of solid tumors.

In an effort to develop a Bcl-2 inhibitor that inhibits all 6 of the pro-survival proteins, Coronado Biosciences utilized an elegant rational drug discovery and design process focused on a structure/activity relationship to originate additional apogossypol-derived compounds. Known as the 5, 5’ derivatives, these third-generation compounds are designed to provide increased potency, enhanced efficacy, and improved pharmaceutical properties.

Of the 5, 5’ derivatives, Coronado Biosciences has established the 8r compound as the lead clinical compound. Early research shows that 8r possesses several advantages over its parent compounds and competitor approaches, including:

• Enhanced potency: 8r appears to be as much as 10 times as potent than parent compound apogossypol
• Broad spectrum therapeutic efficacy: 8r inhibits all 6 of the Bcl-2 pro-survival proteins; note that the parent compounds do not inhibit Bfl-1
• Improved pharmaceutical properties: Better stability and solubility improve oral administration potential
• Solid, unique intellectual property attributes: Composition of matter patent was filed in 2009

Coronado Biosciences intends to file an IND and initiate US clinical trials of 8r in 2011. The 8r candidate shows promise in the treatment of several cancers, including NSCLC, leukemia, lymphoma, and prostate cancer and may potentially be used in conjunction with chemotherapy or radiation therapy to avoid cancer becoming resistant to treatment.