Cancer selective cell death induction by a bivalent CK2 inhibitor targeting the ATP site and the allosteric αD pocket

Bancet, Alexandre; Frem, Rita; Jeanneret, Florian; Mularoni, Angélique; Bazelle, Pauline; Roelants, Caroline; Delcros, Jean-Guy; Guichou, Jean-François; Pillet, Catherine; Coste, Isabelle; Renno, Toufic; Battail, Christophe; Cochet, Claude; Lomberget, Thierry; Filhol, Odile; Krimm, Isabelle

doi:10.1016/j.isci.2024.108903

Cited by 5 publications

(5 citation statements)

References 86 publications

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“…The promising selectivity and biological data suggest that the unique binding mode of CAM4066 serves as an effective strategy for achieving potent selectivity and good inhibition when developing kinase inhibitors. 23, which also binds to the αD pocket and ATP site [136]. AB668 was screened against a panel of 468 kinases at a concentration of 2 μM, and only one other kinase (RPS6KA5) displayed a percentage inhibition above 50%.…”

Section: Inhibitors Acting In the αD Sitementioning

confidence: 99%

“…Additionally, molecular modeling and Xray crystallography of the peptide sequence revealed a single point mutation within the central region of Pc, namely Ile192 to Trp. Using copper-catalyzed azide-alkyne 23, which also binds to the αD pocket and ATP site [136]. AB668 was screened against a panel of 468 kinases at a concentration of 2 µM, and only one other kinase (RPS6KA5) displayed a percentage inhibition above 50%.…”

Section: Holoenzyme Assembly Inhibitionmentioning

confidence: 99%

“…(A) Structure of CAM4066 37; the ATP site binder is highlighted in green and the αD site binder is highlighted in blue; (B) crystal structure of CAM4066 bound to CK2α ATP and αD sites; bonding interactions are shown in magenta; red points indicate the presence of a water molecule (PDB 5CU3); (C) structure of AB668 38; the ATP site binder is highlighted in green and the αD site binder is highlighted in blue. Bancet et al recently discovered AB668 38 (K i = 41 nM, IC 50 = 65 nM), Figure23, which also binds to the αD pocket and ATP site[136]. AB668 was screened against a panel of 468 kinases at a concentration of 2 µM, and only one other kinase (RPS6KA5) displayed a percentage inhibition above 50%.…”

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confidence: 99%

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CK2 Inhibitors Targeting Inside and Outside the Catalytic Box

Day-Riley,

West,

Brear

et al. 2024

Kinases and Phosphatases

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CK2 is a protein kinase that plays an important role in numerous cellular pathways involved in cell growth, differentiation, proliferation, and death. Consequently, upregulation of CK2 is implicated in many disease types, in particular cancer. As such, CK2 has gained significant attention as a potential therapeutic target in cancer, and over 40 chemical probes targeting CK2 have been developed in the past decade. In this review, we highlighted several chemical probes that target sites outside the conventional ATP-binding site. These chemical probes belong to different classes of molecules, from small molecules to peptides, and possess different mechanisms of action. Many of the chemical probes discussed in this review could serve as promising new candidates for drugs selectively targeting CK2.

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Section: Inhibitors Acting In the αD Sitementioning

confidence: 99%

Section: Holoenzyme Assembly Inhibitionmentioning

confidence: 99%

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confidence: 99%

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CK2 Inhibitors Targeting Inside and Outside the Catalytic Box

Day-Riley,

West,

Brear

et al. 2024

Kinases and Phosphatases

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“…23 More recently, the inhibitor AB668 demonstrated that bivalent compounds targeting the ATP site back pocket and the αD pocket simultaneously can have excellent selectivity and potency and induce apoptotic cell death in several cancer cell lines. 39 Although AB668 targets the ATP site, it does not form the canonical hinge hydrogen bonds required for high potency of ATP-competitive orthosteric inhibitors. In this study, we aim to investigate if αD pocket targeting moieties could be linked to ATP mimetic scaffolds.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of chemical linchpins for highly selective CK2α targeting

Greco,

Krämer,

Wahl

et al. 2024

Preprint

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Casein kinase-2 (CK2) are serine/threonine kinases with dual co-factor (ATP and GTP) specificity, that are involved in the regulation of a wide variety of cellular functions. Small molecules targeting CK2 have been described in the literature targeting different binding pockets of the kinase with a focus on type I inhibitors such as the recently published chemical probe SGC-CK2-1. In this study, we investigated whether known allosteric inhibitors binding to a pocket adjacent to helix αD could be combined with ATP mimetic moieties defining a novel class of ATP competitive compounds with a unique binding mode. Linking both binding sites requires a chemical linking moiety that would introduce a 90-degree angle between the ATP mimetic ring system and the αD targeting moiety, which was realized using a sulfonamide. The synthesized inhibitors were highly selective for CK2 with binding constants in the nM range and low micromolar activity. While these inhibitors need to be further improved, the present work provides a structure-based design strategy for highly selective CK2 inhibitors.

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