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Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity

descriptionPublicationkeyboard_double_arrow_right Article 08 Sep 2014 English Publisher:American Chemical Society (ACS)Journal:ACS Medicinal Chemistry Letters, volume 5, pages 1,088-1,093 (issn: 1948-5875, eissn: 1948-5875,

Copyright policy )Funded by:NHMRC | Apoptosis and Stem Cells ..., NHMRC | Mechanisms in Apoptosis a..., NHMRC | Developing novel anti-can... +1 projects

Authors: Michael F. T. Koehler; Guillaume Lessene; Le Wang; Hans E. Purkey; Wayne J. Fairbrother; Anatol Oleksijew; John A. Flygare; +33 Authors

doi: 10.1021/ml5001867

pmid: 25313317

pmc: PMC4190639

Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity

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Abstract

A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization.

Related Organizations

GENENTECH INC
United States
AbbVie Inc.
United States
Walter and Eliza Hall Institute of Medical Research
Australia
University of Melbourne
Australia

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Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity

Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity

7 Research products, page 1 of 1

Construcción y evaluación de vectores pBiFC para el estudio de las interacciones entre las proteínas Bim, PUMA y Noxa y otras proteínas de la familia Bcl-2 y estudio del potencial terapéutico de compuestos miméticos de BH3

Bcl-2-like protein 1

Malignant pleural mesothelioma co-opts BCL-XL and autophagy to escape apoptosis

4QVX

4QVX

BindingDB Entry 50044796: Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity.

Structure-Based Design of A-1293102, a Potent and Selective BCL-XL Inhibitor

Structure-Based Design of A-1293102, a Potent and Selective BCL-X_L Inhibitor