Dual Src and Abl inhibitors target wild type Abl and the AblT315I Imatinib-resistant mutant with different mechanisms

Emmanuele Crespan; Marco Radi; Samantha Zanoli; Silvia Schenone; Maurizio Botta; Giovanni Maga

doi:10.1016/j.bmc.2010.04.024

Dual Src and Abl inhibitors target wild type Abl and the AblT315I Imatinib-resistant mutant with different mechanisms

Bioorg Med Chem. 2010 Jun 1;18(11):3999-4008. doi: 10.1016/j.bmc.2010.04.024. Epub 2010 Apr 18.

Authors

Emmanuele Crespan¹, Marco Radi, Samantha Zanoli, Silvia Schenone, Maurizio Botta, Giovanni Maga

Affiliation

¹ Institute of Molecular Genetics IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy.

PMID: 20451394
DOI: 10.1016/j.bmc.2010.04.024

Abstract

The tyrosine kinase Src and its close homolog Abl, both play important roles in chronic myelogenous leukemia (CML) progression and Imatinib resistance. No clinically approved inhibitors of the drug-resistant AblT315I exist to date. Here, we present a thorough kinetic analysis of two potent dual Src-Abl inhibitors towards wild type Src and Abl, and the AblT315I mutant. Our results show that the most potent compound BO1 shows only a modest loss of potency (fourfold) towards the AblT315I mutant in vitro and was an ATP-competitive inhibitor of wild type Abl but it acted as a non-competitive inhibitor in the case of AblT315I.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate
Benzamides
Drug Resistance, Neoplasm
Humans
Imatinib Mesylate
Kinetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
Mutant Proteins / antagonists & inhibitors*
Mutation, Missense
Piperazines / pharmacology
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
Pyrimidines / pharmacology
src-Family Kinases / antagonists & inhibitors*

Substances

Benzamides
Mutant Proteins
Piperazines
Protein Kinase Inhibitors
Pyrimidines
Imatinib Mesylate
Adenosine Triphosphate
Proto-Oncogene Proteins c-abl
src-Family Kinases