Universität zu Köln

Hochscherf, Jennifer ORCID: 0000-0002-4412-7391, Lindenblatt, Dirk, Witulski, Benedict, Birus, Robin, Aichele, Dagmar, Marminon, Christelle ORCID: 0000-0002-4043-3949, Bouaziz, Zouhair, Le Borgne, Marc ORCID: 0000-0003-1398-075X, Jose, Joachim and Niefind, Karsten ORCID: 0000-0002-0183-6315 (2017). 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 CK2 alpha and Its Paralog CK2 alpha '. Pharmaceuticals, 10 (4). BASEL: MDPI. ISSN 1424-8247

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Abstract

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 (IC50 = 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 CK2 alpha and CK2 alpha', the paralogs of human CK2 catalytic subunit. As expected, 4p occupies the narrow, hydrophobic ATP site of CK2 alpha/CK2 alpha', 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 CK2 alpha structures, but never as a critical mediator of ligand binding. This unexpected binding mode is independent of the interdomain hinge/helix alpha D region conformation and of the salt content in the crystallization medium.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hochscherf, Jennifer UNSPECIFIED orcid.org/0000-0002-4412-7391 UNSPECIFIED Lindenblatt, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Witulski, Benedict UNSPECIFIED UNSPECIFIED UNSPECIFIED Birus, Robin UNSPECIFIED UNSPECIFIED UNSPECIFIED Aichele, Dagmar UNSPECIFIED UNSPECIFIED UNSPECIFIED Marminon, Christelle UNSPECIFIED orcid.org/0000-0002-4043-3949 UNSPECIFIED Bouaziz, Zouhair UNSPECIFIED UNSPECIFIED UNSPECIFIED Le Borgne, Marc UNSPECIFIED orcid.org/0000-0003-1398-075X UNSPECIFIED Jose, Joachim UNSPECIFIED UNSPECIFIED UNSPECIFIED Niefind, Karsten UNSPECIFIED orcid.org/0000-0002-0183-6315 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-208764
DOI:	10.3390/ph10040098
Journal or Publication Title:	Pharmaceuticals
Volume:	10
Number:	4
Date:	2017
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	1424-8247
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DRUG PERMEABILITY; CRYSTAL-STRUCTURE; KAPPA-B; CELL; ATP; SITE; RECOGNITION; DERIVATIVES; HOLOENZYME; FEATURES Multiple languages Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/20876