Closantel is an allosteric inhibitor of human Taspase1

Abstract

Dimerization of Taspase1 activates an intrinsic serine protease function that leads to the catalytic Thr234 residue, which allows to catalyze the consensus sequence Q À3 X À2 D À1 ,G 1 X 2 D 3 D 4 , present in Trithorax family members and TFIIA. Noteworthy, Taspase1 performs only a single hydrolytic step on substrate proteins, which makes it impossible to screen for inhibitors in a classical screening approach. Here, we report the development of an HTRF reporter assay that allowed the identification of an inhibitor, Closantel sodium, that inhibits Taspase1 in a noncovalent fashion (IC 50 = 1.6 mM). The novel inhibitor interferes with the dimerization step and/or the intrinsic serine protease function of the proenzyme. Of interest, Taspase1 is required to activate the oncogenic functions of the leukemogenic AF4-MLL fusion protein and was shown in several studies to be overexpressed in many solid tumors. Therefore, the inhibitor may be useful for further validation of Taspase1 as a target for cancer therapy.

Synergistic antibacterial effects of closantel and its enantiomers in combination with colistin against multidrug resistant gram-negative bacteria

“…It highlights the significance of CLO in controlling the global spread of plasmid-mediated CST resistance. More recent studies have identified CLO as a novel allosteric inhibitor of human Taspase1 (Luciano et al, 2021). All these reports show the importance of reuse old drugs under the circumstances that the development of new drugs is becoming more and more difficult.…”