In this study, we developed and evaluated small molecule inhibitors of Taspase1 as a new candidate class of therapeutic modalities.
Genetic deletion of Taspase1 in the mouse produced no overt deficiencies, suggesting the possibility of a wide therapeutic index for use of Taspase1 inhibitors in cancers.
We defined the peptidyl motifs recognized by Taspase1 and conducted a cell-based dual-fluorescent proteolytic screen of the National Cancer Institute diversity library to identify Taspase1 inhibitors (TASPIN). On the basis of secondary and tertiary screens the 4-[(4-arsonophenyl)methyl]phenyl] arsonic acid NSC48300 was determined to be the most specific active compound. Structure-activity relationship studies indicated a crucial role for the arsenic acid moiety in mediating Taspase1 inhibition.
Additional fluorescence resonance energy transfer-based kinetic analysis characterized NSC48300 as a reversible, noncompetitive inhibitor of Taspase1 (K(i) = 4.22 μmol/L). In the MMTV-neu mouse model of breast cancer and the U251 xenograft model of brain cancer, NSC48300 produced effective tumor growth inhibition.
Our results offer an initial preclinical proof-of-concept to develop TASPINs for cancer therapy.
Cancer Res (1538-7445)
Department of Medicine, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri, USA.
Cancer Res. 2012 Feb;72(3):736-46
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