title: Mimicking the BH3 domain to kill cancer cells.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ni Chonghaile
authors.forename: A
authors.initials: A
authors.lastname: Letai
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000737:chemistry / Q000627:therapeutic use; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D002986:Clinical Trials as Topic; D019281:Dimerization; D016503:Drug Delivery Systems; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009596:Nitrophenols / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000502:physiology; D011758:Pyrroles / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013450:Sulfones / Q000737:chemistry / Q000627:therapeutic use; D013873:Thionucleotides / Q000737:chemistry / Q000627:therapeutic use
chemical_list: C501332:ABT-737; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001549:Benzamides; D001713:Biphenyl Compounds; D007211:Indoles; D009363:Neoplasm Proteins; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D013449:Sulfonamides; D013450:Sulfones; C515128:TW-37 compound; D013873:Thionucleotides; C408162:oblimersen; C520962:obatoclax; C528561:navitoclax