A Pharmacological Inhibitor of the Protease Taspase1 Effectively Inhibits Breast and Brain Tumor Growth
Menée à l'aide de modèles murins, cette étude évalue la faisabilité de développer des inhibiteurs de l'enzyme Taspase1 pour le traitement des cancers du sein et du système nerveux central
The threonine endopeptidase Taspase1 has a critical role in cancer cell proliferation and apoptosis. 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 NCI diversity library to identify Taspase1 inhibitors (TASPINs). Based on 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 FRET-based kinetic analysis characterized NSC48300 as a reversible, non-competitive inhibitor of Taspase1 (KI = 4.22 mM). 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.