An inhibitor of Bcl-2 family proteins induces regression of solid tumours.
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.
Oltersdorf
Tilman
T
Idun Pharmaceuticals, 9380 Judicial Drive, San Diego, California 92121, USA.
Elmore
Steven W
SW
Shoemaker
Alexander R
AR
Armstrong
Robert C
RC
Augeri
David J
DJ
Belli
Barbara A
BA
Bruncko
Milan
M
Deckwerth
Thomas L
TL
Dinges
Jurgen
J
Hajduk
Philip J
PJ
Joseph
Mary K
MK
Kitada
Shinichi
S
Korsmeyer
Stanley J
SJ
Kunzer
Aaron R
AR
Letai
Anthony
A
Li
Chi
C
Mitten
Michael J
MJ
Nettesheim
David G
DG
Ng
ShiChung
S
Nimmer
Paul M
PM
O'Connor
Jacqueline M
JM
Oleksijew
Anatol
A
Petros
Andrew M
AM
Reed
John C
JC
Shen
Wang
W
Tahir
Stephen K
SK
Thompson
Craig B
CB
Tomaselli
Kevin J
KJ
Wang
Baole
B
Wendt
Michael D
MD
Zhang
Haichao
H
Fesik
Stephen W
SW
Rosenberg
Saul H
SH
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
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