Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL.
Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.
Bruncko
Milan
M
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.
Oost
Thorsten K
TK
Belli
Barbara A
BA
Ding
Hong
H
Joseph
Mary K
MK
Kunzer
Aaron
A
Martineau
Darlene
D
McClellan
William J
WJ
Mitten
Michael
M
Ng
Shi-Chung
SC
Nimmer
Paul M
PM
Oltersdorf
Tilman
T
Park
Cheol-Min
CM
Petros
Andrew M
AM
Shoemaker
Alexander R
AR
Song
Xiaohong
X
Wang
Xilu
X
Wendt
Michael D
MD
Zhang
Haichao
H
Fesik
Stephen W
SW
Rosenberg
Saul H
SH
Elmore
Steven W
SW
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008223:Lymphoma; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D009596:Nitrophenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000737:chemistry
C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein