title: An inhibitor of Bcl-2 family proteins induces regression of solid tumours.
abstract: Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice.
authors.affiliation: Idun Pharmaceuticals, 9380 Judicial Drive, San Diego, California 92121, USA.
authors.forename: Tilman
authors.initials: T
authors.lastname: Oltersdorf
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Shoemaker
authors.forename: Robert C
authors.initials: RC
authors.lastname: Armstrong
authors.forename: David J
authors.initials: DJ
authors.lastname: Augeri
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Belli
authors.forename: Milan
authors.initials: M
authors.lastname: Bruncko
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Deckwerth
authors.forename: Jurgen
authors.initials: J
authors.lastname: Dinges
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hajduk
authors.forename: Mary K
authors.initials: MK
authors.lastname: Joseph
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kitada
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Korsmeyer
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Kunzer
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.forename: Chi
authors.initials: C
authors.lastname: Li
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mitten
authors.forename: David G
authors.initials: DG
authors.lastname: Nettesheim
authors.forename: ShiChung
authors.initials: S
authors.lastname: Ng
authors.forename: Paul M
authors.initials: PM
authors.lastname: Nimmer
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: O'Connor
authors.forename: Anatol
authors.initials: A
authors.lastname: Oleksijew
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Petros
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Wang
authors.initials: W
authors.lastname: Shen
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Tahir
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tomaselli
authors.forename: Baole
authors.initials: B
authors.lastname: Wang
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wendt
authors.forename: Haichao
authors.initials: H
authors.lastname: Zhang
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D009596:Nitrophenols; D017239:Paclitaxel / Q000494:pharmacology; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000145:classification* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides; D015996:Survival Rate
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D045304:Cytochromes c; D017239:Paclitaxel