Design of chimeric histone deacetylase- and tyrosine kinase-inhibitors: a series of imatinib hybrides as potent inhibitors of wild-type and mutant BCR-ABL, PDGF-Rbeta, and histone deacetylases

Siavosh Mahboobi; Stefan Dove; Andreas Sellmer; Matthias Winkler; Emerich Eichhorn; Herwig Pongratz; Thomas Ciossek; Thomas Baer; Thomas Maier; Thomas Beckers

doi:10.1021/jm800988r

Design of chimeric histone deacetylase- and tyrosine kinase-inhibitors: a series of imatinib hybrides as potent inhibitors of wild-type and mutant BCR-ABL, PDGF-Rbeta, and histone deacetylases

J Med Chem. 2009 Apr 23;52(8):2265-79. doi: 10.1021/jm800988r.

Authors

Siavosh Mahboobi¹, Stefan Dove, Andreas Sellmer, Matthias Winkler, Emerich Eichhorn, Herwig Pongratz, Thomas Ciossek, Thomas Baer, Thomas Maier, Thomas Beckers

Affiliation

¹ Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany. siavosh.mahboobi@chemie.uni-regensburg.de

PMID: 19301902
DOI: 10.1021/jm800988r

Abstract

Inhibitors of histone deacetylases are a new class of cancer therapeutics with possibly broad applicability. Combinations of HDAC inhibitors with the kinase inhibitor 1 (Imatinib) in recent studies showed additive and synergistic effects. Here we present a new concept by combining inhibition of protein kinases and HDACs, two independent pharmacological activities, in one synthetic small molecule. In general, the HDAC inhibition profile, the potencies, and the probable binding modes to HDAC1 and HDAC6 were similar as for 6 (SAHA). Inhibition of Abl kinase in biochemical assays was maintained for most compounds, but in general the kinase selectivity profile differed from that of 1 with nearly equipotent inhibition of the wild-type and the Imatinib resistant Abl T(315)I mutant. A potent cellular inhibition of PDGFR and cytotoxicity toward EOL-1 cells, a model for idiopathic hypereosinophilic syndrome (HES), are restored or enhanced for selected analogues (12b, 14b, and 18b). Cytotoxicity was evaluated by using a broad panel of tumor cell lines, with selected analogues displaying mean IC(50) values between 3.6 and 7.1 muM.

MeSH terms

Acetylation
Benzamides / chemical synthesis*
Benzamides / chemistry
Benzamides / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Fusion Proteins, bcr-abl
Histone Deacetylase Inhibitors*
Histones / metabolism
Humans
Imatinib Mesylate
Models, Molecular
Mutation
Phthalic Acids / chemical synthesis*
Phthalic Acids / chemistry
Phthalic Acids / pharmacology
Piperazines / chemical synthesis*
Piperazines / chemistry
Piperazines / pharmacology
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / genetics
Pyrimidines / chemical synthesis*
Pyrimidines / chemistry
Pyrimidines / pharmacology
Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors*
Receptor, Platelet-Derived Growth Factor beta / genetics
Stereoisomerism
Structure-Activity Relationship
Thiazoles / chemical synthesis*
Thiazoles / chemistry
Thiazoles / pharmacology
Thiophenes / chemical synthesis*
Thiophenes / chemistry
Thiophenes / pharmacology

Substances

4-(3-(hydroxyamino)-3-oxoprop-1-enyl)-N-(4-methyl-3-(4-(pyridin-3-yl)thiazol-2-ylamino)phenyl)benzamide
Benzamides
Histone Deacetylase Inhibitors
Histones
N1-(2-aminophenyl)-N4-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)terephthalamide
N2-(2-aminophenyl)-N5-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)thiophene-2,5-dicarboxamide
Phthalic Acids
Piperazines
Pyrimidines
Thiazoles
Thiophenes
Imatinib Mesylate
Protein-Tyrosine Kinases
Receptor, Platelet-Derived Growth Factor beta
Fusion Proteins, bcr-abl