Choose a compound to investigate
Oral Pan-BCL-2 Inhibitors
(CNDO103 [apogossypol], CNDO113, CNDO123)
| We believe that the future of cancer therapy lies in oral therapy that not only treats the disease but also simplifies cancer care and improves the ability of patients to live a normal life. The compounds in development as part of Coronado’s Bcl-2 program reflect this belief. |
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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.
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Diagram 2 - Tumor expression in disease types. |
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In many cancer types, over-expression (elevated production) of the Bcl-2 pro-survival proteinsresults 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.. CNDO103 targets 5 of the 6 pro-survival Bcl-2 proteins. This, pan-Bcl-2 inhibitor is optimally designed to complement and be used in combination with existing treatment strategies. In pre-clinical studies, CNDO103 (apogossypol) appears to be potent when used alone and promotes improved efficacy when used in combination with other cytotoxic compounds In vivo pre-clinical studies with CNDO103 demonstrate equivalent potency compared to the parent compound without dose-limiting gastrointestinal and hepatic (liver) toxicities.
Coronado has other oral pan-Bcl-2 inhibitors in development. Utilizing an elegant rational drug discovery and design process that focuses on a structure/activity relationship, Coronado has identified 3 additional clinical candidates, including CNDO113 and CNDO123, two members of a new family of compounds that are distinct from the apogossypol family of compounds, CNDO103 and CNDO133.
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