Discovery and structure-activity relationship of antagonists of B-cell lymphoma 2 family proteins with chemopotentiation activity in vitro and in vivo.
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.
Wendt
Michael D
MD
Cancer Research, Global Pharmaceutical R & D, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. mike.d.wendt@abbott.com
Shen
Wang
W
Kunzer
Aaron
A
McClellan
William J
WJ
Bruncko
Milan
M
Oost
Thorsten K
TK
Ding
Hong
H
Joseph
Mary K
MK
Zhang
Haichao
H
Nimmer
Paul M
PM
Ng
Shi-Chung
SC
Shoemaker
Alexander R
AR
Petros
Andrew M
AM
Oleksijew
Anatol
A
Marsh
Kennan
K
Bauch
Joy
J
Oltersdorf
Tilman
T
Belli
Barbara A
BA
Martineau
Darlene
D
Fesik
Stephen W
SW
Rosenberg
Saul H
SH
Elmore
Steven W
SW
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
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