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.
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.
Mahboobi
Siavosh
S
Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany. siavosh.mahboobi@chemie.uni-regensburg.de
Dove
Stefan
S
Sellmer
Andreas
A
Winkler
Matthias
M
Eichhorn
Emerich
E
Pongratz
Herwig
H
Ciossek
Thomas
T
Baer
Thomas
T
Maier
Thomas
T
Beckers
Thomas
T
D000107:Acetylation; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D008958:Models, Molecular; D009154:Mutation; D010795:Phthalic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C540332:4-(3-(hydroxyamino)-3-oxoprop-1-enyl)-N-(4-methyl-3-(4-(pyridin-3-yl)thiazol-2-ylamino)phenyl)benzamide; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C540330:N1-(2-aminophenyl)-N4-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)terephthalamide; C540331:N2-(2-aminophenyl)-N5-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)thiophene-2,5-dicarboxamide; D010795:Phthalic Acids; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D013876:Thiophenes; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D016044:Fusion Proteins, bcr-abl