Closantel is an allosteric inhibitor of human Taspase1

Vanessa Luciano; Ewgenij Proschak; Julian D Langer; Stefan Knapp; Jan Heering; Rolf Marschalek

doi:10.1016/j.isci.2021.103524

Closantel is an allosteric inhibitor of human Taspase1

iScience. 2021 Nov 27;24(12):103524. doi: 10.1016/j.isci.2021.103524. eCollection 2021 Dec 17.

Authors

Vanessa Luciano¹, Ewgenij Proschak², Julian D Langer³, Stefan Knapp², Jan Heering⁴, Rolf Marschalek¹

Affiliations

¹ Institute of Pharmaceutical Biology/DCAL, Goethe-University of Frankfurt, Biocenter, Max-von-Laue-Street 9, 60438 Frankfurt/Main, Germany.
² Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Biocenter, Max-von-Laue-Street 9, 60438 Frankfurt/Main, Germany.
³ MPI for Biophysics, Max-von-Laue-Street 3, 60438 Frankfurt/Main, Germany.
⁴ Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt/Main, Germany.

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^-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.

Keywords: Biochemistry; Biophysical chemistry; Structural biology.