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

doi:10.1038/nchembio760

Allosteric inhibitors of Bcr-abl-dependent cell proliferation

Nat Chem Biol. 2006 Feb;2(2):95-102. doi: 10.1038/nchembio760. Epub 2006 Jan 15.

Authors

Francisco J Adrián¹, 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

Affiliation

¹ Biological Chemistry Department, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.

PMID: 16415863
DOI: 10.1038/nchembio760

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.

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Apoptosis
Benzamides
Cell Line
Cell Line, Transformed
Cell Proliferation / drug effects
Drug Resistance, Neoplasm
Fusion Proteins, bcr-abl / antagonists & inhibitors
Fusion Proteins, bcr-abl / chemistry
Fusion Proteins, bcr-abl / metabolism
Humans
Imatinib Mesylate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
Mice
Piperazines / pharmacology*
Protein Binding
Protein Conformation
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Pyrimidines / pharmacology*

Substances

Antineoplastic Agents
Benzamides
GNF-2 compound
Piperazines
Protein Kinase Inhibitors
Pyrimidines
Imatinib Mesylate
Protein-Tyrosine Kinases
Fusion Proteins, bcr-abl

Associated data

PubChem-Substance/7980923
PubChem-Substance/7980924
PubChem-Substance/7980925
PubChem-Substance/7980926
PubChem-Substance/7980927
PubChem-Substance/7980928
PubChem-Substance/7980929
PubChem-Substance/7980930
PubChem-Substance/7980931
PubChem-Substance/7982027