Unexpected Binding Mode of a Potent Indeno[1,2-b]indole-Type Inhibitor of Protein Kinase CK2 Revealed by Complex Structures with the Catalytic Subunit CK2α and Its Paralog CK2α′

Jennifer Hochscherf , Dirk Lindenblatt , Benedict Witulski , Robin Birus , Dagmar Aichele (1) , Christelle Marminon (2) , Zouhair Bouaziz (2) , Marc Le Borgne (2) , Joachim Jose (1) , Karsten Niefind

1 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
2 B2MC - Molécules bioactives et chimie médicinale

Protein kinase CK2, a member of the eukaryotic protein kinase superfamily, is associated with cancer and other human pathologies and thus an attractive drug target. The indeno[1,2-b]indole scaffold is a novel lead structure to develop ATP-competitive CK2 inhibitors. Some indeno[1,2-b]indole-based CK2 inhibitors additionally obstruct ABCG2, an ABC half transporter overexpressed in breast cancer and co-responsible for drug efflux and resistance. Comprehensive derivatization studies revealed substitutions of the indeno[1,2-b]indole framework that boost either the CK2 or the ABCG2 selectivity or even support the dual inhibition potential. The best indeno[1,2-b]indole-based CK2 inhibitor described yet (IC 50 = 25 nM) is 5-isopropyl-4-(3-methylbut-2-enyl-oxy)-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (4p). Herein, we demonstrate the membrane permeability of 4p and describe co-crystal structures of 4p with CK2α and CK2α , the paralogs of human CK2 catalytic subunit. As expected, 4p occupies the narrow, hydrophobic ATP site of CK2α/CK2α , but surprisingly with a unique orientation: its hydrophobic substituents point towards the solvent while its two oxo groups are hydrogen-bonded to a hidden water molecule. An equivalent water molecule was found in many CK2α structures, but never as a critical mediator of ligand binding. This unexpected binding mode is independent of the interdomain hinge/helix αD region conformation and of the salt content in the crystallization medium.

Mots clés: ATP-competitive inhibitors; 2-b]indole scaffold; membrane permeability; indeno[1; paralogous isoforms CK2α and CK2α; dual inhibitors; protein kinase CK2; casein kinase 2

Domaines: Chimie thérapeutique; Cristallographie; Cancer; Sciences pharmaceutiques; Biologie structurale [q-bio.BM]

Jennifer Hochscherf, Dirk Lindenblatt, Benedict Witulski, Robin Birus, Dagmar Aichele, et al.. Unexpected Binding Mode of a Potent Indeno[1,2-b]indole-Type Inhibitor of Protein Kinase CK2 Revealed by Complex Structures with the Catalytic Subunit CK2α and Its Paralog CK2α′. Pharmaceuticals, 2017, 10 ((4)98), ⟨10.3390/ph10040098⟩. ⟨hal-01683237⟩