Closantel is an allosteric inhibitor of human Taspase1

iScience

Jan Heering¹  Vanessa Luciano²  Rolf Marschalek²  Ewgenij Proschak³  Stefan Knapp³  Julian D. Langer⁴ 

[1] Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt/Main, Germany;Institute of Pharmaceutical Biology/DCAL, Goethe-University of Frankfurt, Biocenter, Max-von-Laue-Street 9, 60438 Frankfurt/Main, Germany;Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Biocenter, Max-von-Laue-Street 9, 60438 Frankfurt/Main, Germany;MPI for Biophysics, Max-von-Laue-Street 3, 60438 Frankfurt/Main, Germany;

关键词: Biochemistry;    Structural biology;    Biophysical chemistry;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: Dimerization of Taspase1 activates an intrinsic serine protease function that leads to the catalytic Thr234 residue, which allows to catalyze the consensus sequence Q−3X−2D−1⋅G1X2D3D4, 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 (IC50 = 1.6 μM). 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.

【 授权许可】

Unknown