BH3 mimetics to improve cancer therapy; mechanisms and examples.
Tumor cell survival is highly dependent on the expression of certain pro-survival Bcl-2 family proteins. An attractive therapeutic approach is to inhibit these proteins using agents that mimic the Bcl-2 homology 3 (BH3) domains of the proapoptotic Bcl-2 family members, which neutralize these proteins by binding to their surface hydrophobic grooves. A number of BH3 mimetic peptides and small molecules have been described, a few of which have advanced into clinical trials. Recent studies have highlighted ABT-737, a bona fide BH3 mimetic and potent inhibitor of antiapoptotic Bcl-2 family members, as a promising anticancer agent. This review summarizes recent advances in understanding the mechanisms of action of BH3 domains and several classes of BH3 mimetics, as well as the prospects of using these agents to improve cancer therapy.
Zhang
Lin
L
University of Pittsburgh Cancer Institute, Departments of Pharmacology and Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. zhanglx@upmc.edu
Ming
Lihua
L
Yu
Jian
J
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D015507:Drugs, Investigational / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009596:Nitrophenols / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D015507:Drugs, Investigational; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein