Mahboobi, Siavosh and Dove, Stefan and Sellmer, Andreas and Winkler, Matthias and Eichhorn, Emerich and Pongratz, Herwig and Ciossek, Thomas and Baer, Thomas and Maier, Thomas and Beckers, Thomas (2009) 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-R beta, and Histone Deacetylases. JOURNAL OF MEDICINAL CHEMISTRY, 52 (8). pp. 2265-2279. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)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 (Imatimb) 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 AN kinase in biochemical assays was maintained for Most compounds, but in general the kinase selectivity profile differed from that of I with nearly equipotent inhibition of the wildtype and the Imatimb resistant Abl (TI)-I-315 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 IC50 values between 3.6 and 7.1 mu M.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SUBEROYLANILIDE HYDROXAMIC ACID; PHENYLAMINO-PYRIMIDINE PAP; CHRONIC MYELOID-LEUKEMIA; CRYSTAL-STRUCTURE; HDAC INHIBITORS; AURORA KINASES; CELL-LINES; RESISTANCE; CANCER; STI571; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 17 Sep 2020 09:38 |
| Last Modified: | 17 Sep 2020 09:38 |
| URI: | https://pred.uni-regensburg.de/id/eprint/29112 |
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