TY  - JOUR
A1  - Luciano, Vanessa
A1  - Proschak, Ewgenij
A1  - Langer, Julian David
A1  - Knapp, Stefan
A1  - Heering, Jan Peter
A1  - Marschalek, Rolf
T1  - Closantel is an allosteric inhibitor of human Taspase1
T2  - iScience
N2  - 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.
KW  - Biochemistry
KW  - Structural biology
KW  - Biophysical chemistry
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/77910
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-779109
SN  - 2589-0042
VL  - 24
IS  - 12; art. 103524
PB  - Elsevier
CY  - Amsterdam
ER  -