Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins.
Overexpression of prosurvival proteins such as Bcl-2 and Bcl-X L has been correlated with tumorigenesis and resistance to chemotherapy, and thus, the development of antagonists of these proteins may provide a novel means for the treatment of cancer. We recently described the discovery of 1 (ABT-737), which binds Bcl-2, Bcl-X L, and Bcl-w with high affinity, shows robust antitumor activity in murine tumor xenograft models, but is not orally bioavailable. Herein, we report that targeted modifications at three key positions of 1 resulted in a 20-fold improvement in the pharmacokinetic/pharmacodynamic relationship (PK/PD) between oral exposure (AUC) and in vitro efficacy in human tumor cell lines (EC 50). The resulting compound, 2 (ABT-263), is orally efficacious in an established xenograft model of human small cell lung cancer, inducing complete tumor regressions in all animals. Compound 2 is currently in multiple phase 1 clinical trials in patients with small cell lung cancer and hematological malignancies.
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.
Cheol-Min
CM
Park
Milan
M
Bruncko
Jessica
J
Adickes
Joy
J
Bauch
Hong
H
Ding
Aaron
A
Kunzer
Kennan C
KC
Marsh
Paul
P
Nimmer
Alexander R
AR
Shoemaker
Xiaohong
X
Song
Stephen K
SK
Tahir
Christin
C
Tse
Xilu
X
Wang
Michael D
MD
Wendt
Xiufen
X
Yang
Haichao
H
Zhang
Stephen W
SW
Fesik
Saul H
SH
Rosenberg
Steven W
SW
Elmore
D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides