Allosteric inhibitors of Bcr-abl-dependent cell proliferation

Francisco J. Adrián, Qiang Ding, Taebo Sim, Anastasia Velentza, Christine Sloan, Yi Liu, Guobao Zhang, Wooyoung Hur, Sheng Ding, Paul Manley, Jürgen Mestan, Doriano Fabbro, Nathanael S. Gray

Research output: Contribution to journalArticle

251 Citations (Scopus)

Abstract

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism.

Original languageEnglish
Pages (from-to)95-102
Number of pages8
JournalNature Chemical Biology
Volume2
Issue number2
DOIs
Publication statusPublished - 2006 Feb 1
Externally publishedYes

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Phosphotransferases
Cell Proliferation
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Myeloproliferative Disorders
Protein-Tyrosine Kinases
Libraries
Catalytic Domain
Pharmacology
Proteins
Imatinib Mesylate

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Adrián, F. J., Ding, Q., Sim, T., Velentza, A., Sloan, C., Liu, Y., ... Gray, N. S. (2006). Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nature Chemical Biology, 2(2), 95-102. https://doi.org/10.1038/nchembio760

Allosteric inhibitors of Bcr-abl-dependent cell proliferation. / Adrián, Francisco J.; Ding, Qiang; Sim, Taebo; Velentza, Anastasia; Sloan, Christine; Liu, Yi; Zhang, Guobao; Hur, Wooyoung; Ding, Sheng; Manley, Paul; Mestan, Jürgen; Fabbro, Doriano; Gray, Nathanael S.

In: Nature Chemical Biology, Vol. 2, No. 2, 01.02.2006, p. 95-102.

Research output: Contribution to journalArticle

Adrián, FJ, Ding, Q, Sim, T, Velentza, A, Sloan, C, Liu, Y, Zhang, G, Hur, W, Ding, S, Manley, P, Mestan, J, Fabbro, D & Gray, NS 2006, 'Allosteric inhibitors of Bcr-abl-dependent cell proliferation', Nature Chemical Biology, vol. 2, no. 2, pp. 95-102. https://doi.org/10.1038/nchembio760
Adrián FJ, Ding Q, Sim T, Velentza A, Sloan C, Liu Y et al. Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nature Chemical Biology. 2006 Feb 1;2(2):95-102. https://doi.org/10.1038/nchembio760
Adrián, Francisco J. ; Ding, Qiang ; Sim, Taebo ; Velentza, Anastasia ; Sloan, Christine ; Liu, Yi ; Zhang, Guobao ; Hur, Wooyoung ; Ding, Sheng ; Manley, Paul ; Mestan, Jürgen ; Fabbro, Doriano ; Gray, Nathanael S. / Allosteric inhibitors of Bcr-abl-dependent cell proliferation. In: Nature Chemical Biology. 2006 ; Vol. 2, No. 2. pp. 95-102.
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