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DC Field | Value | Language |
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dc.citation.endPage | 6915 | - |
dc.citation.number | 21 | - |
dc.citation.startPage | 6902 | - |
dc.citation.title | JOURNAL OF MEDICINAL CHEMISTRY | - |
dc.citation.volume | 51 | - |
dc.contributor.author | Park, Cheol-Min | - |
dc.contributor.author | Bruncko, Milan | - |
dc.contributor.author | Adickes, Jessica | - |
dc.contributor.author | Bauch, Joy | - |
dc.contributor.author | Ding, Hong | - |
dc.contributor.author | Kunzer, Aaron | - |
dc.contributor.author | Marsh, Kennan C. | - |
dc.contributor.author | Nimmer, Paul | - |
dc.contributor.author | Shoemaker, Alexander R. | - |
dc.contributor.author | Song, Xiaohong | - |
dc.contributor.author | Tahir, Stephen K. | - |
dc.contributor.author | Tse, Christin | - |
dc.contributor.author | Wang, Xilu | - |
dc.contributor.author | Wendt, Michael D. | - |
dc.contributor.author | Yang, Xiufen | - |
dc.contributor.author | Zhang, Haichao | - |
dc.contributor.author | Fesik, Stephen W. | - |
dc.contributor.author | Rosenberg, Saul H. | - |
dc.contributor.author | Elmore, Steven W. | - |
dc.date.accessioned | 2023-12-22T08:16:23Z | - |
dc.date.available | 2023-12-22T08:16:23Z | - |
dc.date.created | 2014-11-10 | - |
dc.date.issued | 2008-11 | - |
dc.description.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. | - |
dc.identifier.bibliographicCitation | JOURNAL OF MEDICINAL CHEMISTRY, v.51, no.21, pp.6902 - 6915 | - |
dc.identifier.doi | 10.1021/jm800669s | - |
dc.identifier.issn | 0022-2623 | - |
dc.identifier.scopusid | 2-s2.0-56249144184 | - |
dc.identifier.uri | https://scholarworks.unist.ac.kr/handle/201301/8545 | - |
dc.identifier.url | http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=56249144184 | - |
dc.identifier.wosid | 000260730900030 | - |
dc.language | 영어 | - |
dc.publisher | AMER CHEMICAL SOC | - |
dc.title | Discovery of an Orally Bioavailable Small Molecule Inhibitor of Prosurvival B-Cell Lymphoma 2 Proteins | - |
dc.type | Article | - |
dc.description.journalRegisteredClass | scopus | - |
dc.subject.keywordPlus | BCL-2 FAMILY-MEMBERS | - |
dc.subject.keywordPlus | BH3 MIMETIC ABT-737 | - |
dc.subject.keywordPlus | SUBSTITUENT CONSTANTS | - |
dc.subject.keywordPlus | APOPTOSIS | - |
dc.subject.keywordPlus | ANTAGONISTS | - |
dc.subject.keywordPlus | BCL-X(L) | - |
dc.subject.keywordPlus | POTENT | - |
dc.subject.keywordPlus | ACTIVATION | - |
dc.subject.keywordPlus | MECHANISMS | - |
dc.subject.keywordPlus | RESISTANCE | - |
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