A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo.
Inhibition of the prosurvival members of the Bcl-2 family of proteins represents an attractive strategy for the treatment of cancer. We have previously reported the activity of ABT-737, a potent inhibitor of Bcl-2, Bcl-X(L), and Bcl-w, which exhibits monotherapy efficacy in xenograft models of small-cell lung cancer and lymphoma and potentiates the activity of numerous cytotoxic agents. Here we describe the biological activity of A-385358, a small molecule with relative selectivity for binding to Bcl-X(L) versus Bcl-2 (K(i)'s of 0.80 and 67 nmol/L for Bcl-X(L) and Bcl-2, respectively). This compound efficiently enters cells and co-localizes with the mitochondrial membrane. Although A-385358 shows relatively modest single-agent cytotoxic activity against most tumor cell lines, it has an EC(50) of <500 nmol/L in cells dependent on Bcl-X(L) for survival. In addition, A-385358 enhances the in vitro cytotoxic activity of numerous chemotherapeutic agents (paclitaxel, etoposide, cisplatin, and doxorubicin) in several tumor cell lines. In A549 non-small-cell lung cancer cells, A-385358 potentiates the activity of paclitaxel by as much as 25-fold. Importantly, A-385358 also potentiated the activity of paclitaxel in vivo. Significant inhibition of tumor growth was observed when A-385358 was added to maximally tolerated or half maximally tolerated doses of paclitaxel in the A549 xenograft model. In tumors, the combination therapy also resulted in a significant increase in mitotic arrest followed by apoptosis relative to paclitaxel monotherapy.
Shoemaker
Alex R
AR
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. alex.shoemaker@abbott.com
Oleksijew
Anatol
A
Bauch
Joy
J
Belli
Barbara A
BA
Borre
Tony
T
Bruncko
Milan
M
Deckwirth
Thomas
T
Frost
David J
DJ
Jarvis
Ken
K
Joseph
Mary K
MK
Marsh
Kennan
K
McClellan
William
W
Nellans
Hugh
H
Ng
ShiChung
S
Nimmer
Paul
P
O'Connor
Jacqueline M
JM
Oltersdorf
Tilman
T
Qing
Weiguo
W
Shen
Wang
W
Stavropoulos
Jason
J
Tahir
Stephen K
SK
Wang
Baole
B
Warner
Robert
R
Zhang
Haichao
H
Fesik
Stephen W
SW
Rosenberg
Saul H
SH
Elmore
Steven W
SW
D000814:Aniline Compounds / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009596:Nitrophenols / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017239:Paclitaxel / Q000493:pharmacokinetics; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*; D000096926:Benzenesulfonamides
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D017239:Paclitaxel; D010879:Piperazines; D013449:Sulfonamides; D051020:bcl-X Protein; C509000:4-(3-dimethylamino-1-phenylsulfanylmethylpropylamino)-N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide; D000096926:Benzenesulfonamides; C501332:ABT-737