Journal Article

PUBDB-2025-04031

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Exploring the biological potential of the brominated indenoindole MC11 and its interaction with protein kinase CK2

Marminon, C. ; Werner, C. ; Gast, A. ; Herfindal, L. ; Charles, J. ; Lindenblatt, D. ; Aichele, D. ; Mularoni, A. ; Døskeland, S. O. ; Jose, J. ; Niefind, K.Extern*EMBL* ; Le Borgne, M. (Corresponding author)

2025

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Please use a persistent id in citations: doi:10.1515/hsz-2024-0160  doi:10.3204/PUBDB-2025-04031

Abstract: Protein kinase CK2 is a promising therapeutic target, especially in oncology. Over the years, various inhibitors have been developed, with polyhalogenated scaffolds emerging as a particularly effective class. Halogens like bromine and chlorine enhance inhibitor stability by forming additional interactions within the ATP pocket. Among halogenated scaffolds, benzotriazole and benzimidazole have led to potent molecules such as 4,5,6,7-tetrabromo-1H-benzotriazole (IC50 = 300 nM) and 4,5,6,7-tetrabromo-2-(dimethylamino)benzimidazole (IC50 = 140 nM). Modifications, including 4,5,6-tribromo-7-ethyl-1H-benzotriazole (IC50 = 160 nM), further improved activity. Changing scaffolds while retaining halogens has enabled design of new inhibitors. Flavonols, dibenzofuranones, and the indeno[1,2-b]indole scaffold are key examples. Halogenation of the reference molecule 5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (4b, IC50 = 360 nM) significantly boosted potency. The study focused on introducing four halogens, yielding to the compound 1,2,3,4-tetrabromo-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (MC11), with an IC50 of 16 nM. Co-crystallography revealed how bromine atoms enhance binding, and MC11 demonstrated strong in cellulo activity, particularly against leukemic cell lines like IPC-Bcl2.

Note: Deutsche Forschungsgemeinschaft (DFG) (grant no. INST 216/682-1 FUGG).

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. DFG project G:(GEPRIS)534044797 - Large Scale Data Facility 3 - Anteil Forschungsgroßgerät (LSDF3-FuGG) (534044797) (534044797)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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