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.
Park
Cheol-Min
CM
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.
Bruncko
Milan
M
Adickes
Jessica
J
Bauch
Joy
J
Ding
Hong
H
Kunzer
Aaron
A
Marsh
Kennan C
KC
Nimmer
Paul
P
Shoemaker
Alexander R
AR
Song
Xiaohong
X
Tahir
Stephen K
SK
Tse
Christin
C
Wang
Xilu
X
Wendt
Michael D
MD
Yang
Xiufen
X
Zhang
Haichao
H
Fesik
Stephen W
SW
Rosenberg
Saul H
SH
Elmore
Steven W
SW
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