title: Discovery and structure-activity relationship of antagonists of B-cell lymphoma 2 family proteins with chemopotentiation activity in vitro and in vivo.
abstract: Development of a rationally designed potentiator of cancer chemotherapy, via inhibition of Bcl-X(L) function, is described. Lead compounds generated by NMR screening and directed parallel synthesis displayed sub-microM binding but were strongly deactivated in the presence of serum. The dominant component of serum deactivation was identified as domain III of human serum albumin (HSA); NMR solution structures of inhibitors bound to both Bcl-X(L) and HSA domain III indicated two potential optimization sites for separation of affinities. Modifications at both sites resulted in compounds with improved Bcl-X(L) binding and greatly increased activity in the presence of human serum, culminating in 73R, which bound to Bcl-X(L) with a K(i) of 0.8 nM. In a cellular assay 73R reversed the protection afforded by Bcl-X(L) overexpression against cytokine deprivation in FL5.12 cells with an EC(50) of 0.47 microM. 73R showed little effect on the viability of the human non small cell lung cancer cell line A549. However, consistent with the proposed mechanism, 73R potentiated the activity of paclitaxel and UV irradiation in vitro and potentiated the antitumor efficacy of paclitaxel in a mouse xenograft model.
authors.affiliation: Cancer Research, Global Pharmaceutical R & D, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. mike.d.wendt@abbott.com
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wendt
authors.forename: Wang
authors.initials: W
authors.lastname: Shen
authors.forename: Aaron
authors.initials: A
authors.lastname: Kunzer
authors.forename: William J
authors.initials: WJ
authors.lastname: McClellan
authors.forename: Milan
authors.initials: M
authors.lastname: Bruncko
authors.forename: Thorsten K
authors.initials: TK
authors.lastname: Oost
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.forename: Mary K
authors.initials: MK
authors.lastname: Joseph
authors.forename: Haichao
authors.initials: H
authors.lastname: Zhang
authors.forename: Paul M
authors.initials: PM
authors.lastname: Nimmer
authors.forename: Shi-Chung
authors.initials: SC
authors.lastname: Ng
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Shoemaker
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Petros
authors.forename: Anatol
authors.initials: A
authors.lastname: Oleksijew
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: Joy
authors.initials: J
authors.lastname: Bauch
authors.forename: Tilman
authors.initials: T
authors.lastname: Oltersdorf
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Belli
authors.forename: Darlene
authors.initials: D
authors.lastname: Martineau
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 / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005454:Fluorescence Polarization; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D016513:Mice, SCID; D017239:Paclitaxel / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D044967:Serum; D012709:Serum Albumin / Q000737:chemistry; D013237:Stereoisomerism; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014466:Ultraviolet Rays; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*; D000096926:Benzenesulfonamides
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D017239:Paclitaxel; D010880:Piperidines; D012709:Serum Albumin; D013449:Sulfonamides; D051020:bcl-X Protein; C509000:4-(3-dimethylamino-1-phenylsulfanylmethylpropylamino)-N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide; D000096926:Benzenesulfonamides