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PMID: 19641500 Published · ppublish English Journal Article Review

Mimicking the BH3 domain to kill cancer cells.

Oncogene ·Vol. 27 Suppl 1 ·2008-12-00 ·Pages S149-57

Ni Chonghaile T, Letai A

Abstract

Cancer cells show deviant behavior that induces apoptotic signaling. To survive, cancer cells typically acquire changes enabling evasion of death signals. One way they do this is by increasing the expression of anti-apoptotic BCL-2 proteins. Anti-apoptotic BCL-2 family proteins antagonize death signaling by forming heterodimers with pro-death proteins. Heterodimer formation occurs through binding of the pro-apoptotic protein's BH3 domain into the hydrophobic cleft of anti-apoptotic proteins. The BH3 mimetics are small molecule antagonists of the anti-apoptotic BCL-2 members that function as competitive inhibitors by binding to the hydrophobic cleft. Under certain conditions, antagonism of anti-apoptotic BCL-2 family proteins can unleash pro-death molecules in cancer cells. Thus, the BH3 mimetics are a new class of cancer drugs that specifically target a mechanism of cancer cell survival to selectively kill cancer cells.

MeSH Terms
Aniline Compounds/chemistry,therapeutic use Animals Antineoplastic Agents/chemistry,classification,pharmacology,therapeutic use Apoptosis/drug effects Benzamides/chemistry,therapeutic use Binding, Competitive Biphenyl Compounds/chemistry,pharmacology Clinical Trials as Topic Dimerization Drug Delivery Systems Drug Design Drug Resistance, Neoplasm Drug Screening Assays, Antitumor Humans Indoles Mice Mitochondria/drug effects,physiology Multigene Family Neoplasm Proteins/antagonists & inhibitors Neoplasms/drug therapy,metabolism Nitrophenols/chemistry,pharmacology Piperazines/chemistry,pharmacology Protein Structure, Tertiary Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors,chemistry,physiology Pyrroles/chemistry,therapeutic use Structure-Activity Relationship Sulfonamides/chemistry,pharmacology,therapeutic use Sulfones/chemistry,therapeutic use Thionucleotides/chemistry,therapeutic use
Chemicals
ABT-737 Aniline Compounds Antineoplastic Agents Benzamides Biphenyl Compounds Indoles Neoplasm Proteins Nitrophenols Piperazines Proto-Oncogene Proteins c-bcl-2 Pyrroles Sulfonamides Sulfones TW-37 compound Thionucleotides oblimersen obatoclax navitoclax
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Ni Chonghaile T
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Letai A
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Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
1476-5594
DOI
10.1038/onc.2009.52
Published
2008-12-00
Pages
S149-57
Language
English
Region
England
NLM ID
8711562
PMCID
PMC3733265
Subset
IM
Grants
NCI NIH HHS · R01 CA129974 · United States
External Links
PubMed source DOI: 10.1038/onc.2009.52 PMC Full Text View journal details
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