title: A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo.
abstract: 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.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. alex.shoemaker@abbott.com
authors.forename: Alex R
authors.initials: AR
authors.lastname: Shoemaker
authors.forename: Anatol
authors.initials: A
authors.lastname: Oleksijew
authors.forename: Joy
authors.initials: J
authors.lastname: Bauch
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Belli
authors.forename: Tony
authors.initials: T
authors.lastname: Borre
authors.forename: Milan
authors.initials: M
authors.lastname: Bruncko
authors.forename: Thomas
authors.initials: T
authors.lastname: Deckwirth
authors.forename: David J
authors.initials: DJ
authors.lastname: Frost
authors.forename: Ken
authors.initials: K
authors.lastname: Jarvis
authors.forename: Mary K
authors.initials: MK
authors.lastname: Joseph
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: William
authors.initials: W
authors.lastname: McClellan
authors.forename: Hugh
authors.initials: H
authors.lastname: Nellans
authors.forename: ShiChung
authors.initials: S
authors.lastname: Ng
authors.forename: Paul
authors.initials: P
authors.lastname: Nimmer
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: O'Connor
authors.forename: Tilman
authors.initials: T
authors.lastname: Oltersdorf
authors.forename: Weiguo
authors.initials: W
authors.lastname: Qing
authors.forename: Wang
authors.initials: W
authors.lastname: Shen
authors.forename: Jason
authors.initials: J
authors.lastname: Stavropoulos
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Tahir
authors.forename: Baole
authors.initials: B
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Warner
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
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
mesh_terms: 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
chemical_list: 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