Broad-Spectrum Anticancer Activity and Pharmacokinetic Properties of a Prenyloxy-Substituted Indeno[1,2-b]indole Derivative, Discovered as CK2 Inhibitor

El-Awaad, Ehab; Birus, Robin; Marminon, Christelle; Bouaziz, Zouhair; Ballentin, Laurens; Aichele, Dagmar; Borgne, Marc Le; Jose, Joachim

doi:10.3390/ph14060542

Cited by 5 publications

(2 citation statements)

References 55 publications

(66 reference statements)

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“…The broad-spectrum anticancer activity of 55 has been evaluated. It inhibited cell proliferation and migration in different types of cancer cells, and the induction of apoptosis was also demonstrated in A431 cells at a concentration of 20 μM . The crystal structure indicates that the binding of 55 mainly depends on extensive hydrophobic embedding.…”

Section: Inhibitors Of Ck2mentioning

confidence: 92%

“…It inhibited cell proliferation and migration in different types of cancer cells, and the induction of apoptosis was also demonstrated in A431 cells at a concentration of 20 μM. 125 The crystal structure indicates that the binding of 55 mainly depends on extensive hydrophobic embedding. Moreover, two carbonyl groups form a complex hydrogen bond network with two conserved water molecules, Lys68, Glu81, and Asp175 (PDB 5ONI, Figure 8C).…”

Section: Inhibitors Of Ck2mentioning

confidence: 99%

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Strategies of Targeting CK2 in Drug Discovery: Challenges, Opportunities, and Emerging Prospects

Chen

Wang

et al. 2023

J. Med. Chem.

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CK2 (casein kinase 2) is a serine/threonine protein kinase that is ubiquitous in eukaryotic cells and plays important roles in a variety of cellular functions, including cell growth, apoptosis, circadian rhythms, DNA damage repair, transcription, and translation. CK2 is involved in cancer pathogenesis and the occurrence of many diseases. Therefore, targeting CK2 is a promising therapeutic strategy. Although many CK2specific small-molecule inhibitors have been developed, only CX-4945 has progressed to clinical trials. In recent years, novel CK2 inhibitors have gradually become a research hotspot, which is expected to overcome the limitations of traditional inhibitors. Herein, we summarize the structure, biological functions, and disease relevance of CK2 and emphatically analyze the structure−activity relationship (SAR) and binding modes of small-molecule CK2 inhibitors. We also discuss the latest progress of novel strategies, providing insights into new drugs targeting CK2 for clinical practice.

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Section: Inhibitors Of Ck2mentioning

confidence: 92%

Section: Inhibitors Of Ck2mentioning

confidence: 99%

Strategies of Targeting CK2 in Drug Discovery: Challenges, Opportunities, and Emerging Prospects

Chen

Wang

et al. 2023

J. Med. Chem.

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4,5,7‐Trisubstituted indeno[1,2‐b]indole inhibits CK2 activity in tumor cells equivalent to CX‐4945 and shows strong anti‐migratory effects

et al. 2021

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Highly pleiotropic and constitutively active protein kinase CK2 is a key target in cancer therapy, but only one small-molecule inhibitor has reached clinical trials-CX-4945. In this study, we present the indeno[1,2-b]indole derivative 5-isopropyl-4-methoxy-7-methyl-5,6,7,8-tetrahydroindeno[1,2-b] indole-9,10-dione (5a-2) that decreased the intracellular CK2 activity in A431, A549, and LNCaP tumor cell lines analogous to CX-4945 (> 75% inhibition at 20 µM) and similarly blocked CK2-specific Akt phosphorylation in LNCaP cells. Cellular uptake analysis demonstrated higher intracellular concentrations of 5a-2 (408.3 nM) compared with . This finding clarifies the comparable effects of both compounds on the intracellular CK2 activity despite their different inhibitory potency in vitro [IC 50 = 25 nM (5a-2) and 3.7 nM (CX-4945)]. Examination of the effects of both CK2 inhibitors on cancer cells using live-cell imaging revealed notable differences. Whereas CX-4945 showed a stronger pro-apoptotic effect on tumor cells, 5a-2 was more effective in inhibiting tumor cell migration. Our results showed that 49% of intracellular CX-4945 was localized in the nuclear fraction, whereas 71% of 5a-2 was detectable in the cytoplasm. The different subcellular distribution, and thus the site of CK2 inhibition, provides a possible explanation for the different cellular effects. Our study indicates that investigating CK2 inhibition-mediated cellular effects in relation to the subcellular sites of CK2 inhibition may help to improve our understanding of the preferential roles of CK2 within different cancer cell compartments.Human protein kinase CK2 is a constitutively active serine/threonine kinase [1]. Today, the enzyme, which was first described in 1954 as 'casein kinase 2', is known to phosphorylate more than 500 substrates [2,3]. Together with an ubiquitous expression in eukaryotic cells [4], this high pleiotropy is the reason

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Palladium‐Catalyzed Tandem Cyclization of 2‐(2 Ethynylphenyl)acetonitriles and Isocyanides: Access to Indeno[2,1‐b]pyrroles

et al. 2022

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Broad-Spectrum Anticancer Activity and Pharmacokinetic Properties of a Prenyloxy-Substituted Indeno[1,2-b]indole Derivative, Discovered as CK2 Inhibitor

Cited by 5 publications

References 55 publications

Strategies of Targeting CK2 in Drug Discovery: Challenges, Opportunities, and Emerging Prospects

Strategies of Targeting CK2 in Drug Discovery: Challenges, Opportunities, and Emerging Prospects

4,5,7‐Trisubstituted indeno[1,2‐b]indole inhibits CK2 activity in tumor cells equivalent to CX‐4945 and shows strong anti‐migratory effects

Palladium‐Catalyzed Tandem Cyclization of 2‐(2 Ethynylphenyl)acetonitriles and Isocyanides: Access to Indeno[2,1‐b]pyrroles

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