Small-molecule inhibitors of Bcl-2.

Abstract

Cancer cells with elevated levels of Bcl-2 and the related anti-apoptotic proteins Bcl-x(L), Mcl-1 and Bcl-W are broadly resistant to standard anticancer drugs and other therapeutic modalities. Antisense oligodeoxynucleotides and, more recently, small-molecule ligands for Bcl-2 and Bcl-x(L), sensitize cancer cells to cytotoxic therapies. In some cases, Bcl-2-targeted therapies can function as single therapeutic agents to kill tumor cells, suggesting that Bcl-2 has an important role in the critical functions of cancer cells. The molecular mechanisms of Bcl-2 are not completely understood, therefore, the validation of cytotoxic mechanisms related to Bcl-2 as well as the identification of surrogate markers for Bcl-2 function are significant obstacles for drug development. Despite these problems, two Bcl-2 small-molecule inhibitors are currently undergoing phase I/II clinical trials and several other compounds are in preclinical development. Ongoing studies with these investigational drugs should provide new insights into optimal strategies to disrupt Bcl-2 survival functions to selectively kill cancer cells.

• Authors: Michael K Manion, John Fry, Pam S Schwartz, David M Hockenbery
• Journal: Current opinion in investigational drugs (London, England : 2000) (Curr Opin Investig Drugs) Vol. 7 Issue 12 Pg. 1077-84 (Dec 2006) ISSN: 1472-4472 [Print] England
• PMID: 17209525 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• Proto-Oncogene Proteins c-bcl-2

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Humans
• Models, Molecular
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Survival