BROWSE

Related Researcher

Author's Photo

Park, Cheol-Min
Synthetic & Medicinal Chemistry Lab
Research Interests
  • Organic synthesis, medicinal chemistry, chemical biology

ITEM VIEW & DOWNLOAD

Discovery of an Orally Bioavailable Small Molecule Inhibitor of Prosurvival B-Cell Lymphoma 2 Proteins

Cited 114 times inthomson ciCited 111 times inthomson ci
Title
Discovery of an Orally Bioavailable Small Molecule Inhibitor of Prosurvival B-Cell Lymphoma 2 Proteins
Author
Park, Cheol-MinBruncko, MilanAdickes, JessicaBauch, JoyDing, HongKunzer, AaronMarsh, Kennan C.Nimmer, PaulShoemaker, Alexander R.Song, XiaohongTahir, Stephen K.Tse, ChristinWang, XiluWendt, Michael D.Yang, XiufenZhang, HaichaoFesik, Stephen W.Rosenberg, Saul H.Elmore, Steven W.
Issue Date
2008-11
Publisher
AMER CHEMICAL SOC
Citation
JOURNAL OF MEDICINAL CHEMISTRY, v.51, no.21, pp.6902 - 6915
Abstract
Overexpression of prosurvival proteins such as Bcl-2 and Bcl-XL 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-XL, 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 (EC50). 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.
URI
https://scholarworks.unist.ac.kr/handle/201301/8545
URL
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=56249144184
DOI
10.1021/jm800669s
ISSN
0022-2623
Appears in Collections:
CHM_Journal Papers
Files in This Item:
There are no files associated with this item.

find_unist can give you direct access to the published full text of this article. (UNISTARs only)

Show full item record

qrcode

  • mendeley

    citeulike

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

MENU