Chimeric tyrosine kinase-HDAC inhibitors as antiproliferative agents.
Combined treatment with tyrosine kinase inhibitors (TKi) and additional drugs is emerging as a promising strategy for cancer therapy. TKi and histone-deacetylase inhibitors (HDI) are two classes of anti-tumor agents with distant mechanisms of action. We have designed and synthesized chimeric compounds, which comprise structural elements of the TKi imatinib, and of prototypical HDI compounds. These compounds retain TKi activity similar to imatinib, exemplified by the inhibition of the platelet-derived growth factor receptor, and c-Kit kinase in intact cells. In addition, the chimeric compounds have in vitro and cellular HDI activity, and potently inhibit growth of cancer cell lines, including that of imatinib-resistant cell lines. Chimeric molecules with combined TKi and HDI activity may simplify combination treatment and be applicable to overcome clinical resistance to TKi single-agent therapy.
Uecker
Andrea
A
Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Friedrich-Schiller-University Jena, Germany.
Sicker
Marit
M
Beckers
Thomas
T
Mahboobi
Siavosh
S
Hägerstrand
Daniel
D
Ostman
Arne
A
Böhmer
Frank-D
FD
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000627:therapeutic use*; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor