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.
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Mahboobi S, Dove S, Sellmer A, Winkler M, Eichhorn E, Pongratz H, Ciossek T, Baer T, Maier T, Beckers T
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.
- PubMed ID
- 19301902 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Imatinib Platelet-derived growth factor receptor beta IC 50 (nM) 240 N/A N/A Details Imatinib Tyrosine-protein kinase ABL1 IC 50 (nM) 1100 N/A N/A Details Vorinostat Histone deacetylase 1 IC 50 (nM) 20 N/A N/A Details Vorinostat Histone deacetylase 6 IC 50 (nM) 52 N/A N/A Details