Small-molecule inhibitors of Bcl-2.
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.
Manion
Michael K
MK
Fred Hutchinson Cancer Research Center, Division of Clinical Research and Human Biology, 1100 Fairview Avenue North, C3-168, Seattle, WA 98109-1024, USA.
Fry
John
J
Schwartz
Pam S
PS
Hockenbery
David M
DM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013534:Survival
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2