A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066

Fusco, Claudia De; Brear, P.; Iegre, Jessica; Georgiou, K.H.; Sore, Hannah F.; Hyvönen, Marko; Spring, David R.

doi:10.1016/j.bmc.2017.04.037

Cited by 59 publications

(107 citation statements)

References 32 publications

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“…Indeed, one such small pocket, termed αD pocket, was identified on the large C-terminal lobe of the catalytic subunit. 18 The most elaborated αD pocket ligand, CAM4712 (MW 453 g/mol), exhibited a moderate potency in the cell-free assay (IC 50 = 7 µM) and good efficacy in cells, while the selectivity over other kinases required further optimization. 19 modulators were investigated and compared to that of the ATP-competitive reference inhibitor CX-4945.…”

Section: Introductionmentioning

confidence: 99%

2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 2. Structure-Based Optimization and Investigation of Effects Specific to the Allosteric Mode of Action

et al. 2019

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Protein CK2 has gained much interest as an anti-cancer drug target in the last decade. We had previously described the identification of a new allosteric site on the catalytic α-subunit, along with first small molecule ligands based on the 4-(4-phenylthiazol-2-ylamino) benzoic acid scaffold. In the present work, structure optimizations guided by a binding model led to the identification of the lead compound 2-hydroxy-4-((4-(naphthalen-2-yl)thiazol-2yl)amino)benzoic acid (27), showing a submicromolar potency against purified CK2α (IC 50 = 0.6 µM). Furthermore, 27 induced apoptosis and cell death in 786-O renal cell carcinoma cells (EC 50 = 5 µM) and inhibited STAT3 activation even more potently than the ATPcompetitive drug candidate CX-4945 (EC 50 s: 1.6 µM vs. 5.3 µM). Notably, the potencies of our allosteric ligands to inhibit CK2 varied depending on the individual substrate. Altogether, the novel allosteric pocket was proved a druggable site, offering an excellent perspective to develop efficient and selective allosteric CK2 inhibitors. Recently, we identified 2-aminothiazole derivatives as novel allosteric inhibitors of CK2α; 20 exemplarily shown are compounds 1-4 (Figure 1). Using complementary methods, it was demonstrated that compound 3 binds in an allosteric pocket adjacent to the ATP binding site, between the glycine-rich loop and the αC-helix. A preliminary hit optimization led to compound 4, exhibiting an IC 50 of 3.4 µM. However, it had yet to be shown that the new CK2 modulator class can be developed further into more potent drugs, which is often a limitation with allosteric target sites that were not evolutionary designed for high-affinity interactions with small molecules. 21, 22 Therefore, we carried out a compound optimization guided by a binding model, as will be described below. The cellular effects of the allosteric CK2

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Section: Introductionmentioning

confidence: 99%

2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 2. Structure-Based Optimization and Investigation of Effects Specific to the Allosteric Mode of Action

et al. 2019

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“…CK2 α/β interface (Site 6 including Tyr 39, Val67, Val112 and Val101) has been confirmed to be occupied by the DRB, W16, CAM187 and cyclic peptide Pc, which antagonize the assembly of CK2 holoenzyme complex [16]. The αD pocket named site 3 was demonstrated as the allosteric pocket to accommodate the biaryl rings of CAM4712 analogues [17][18][19]. Recently, Bestgen et al discovered aminothiazole derivatives as the allosteric modulators of CK2 by targeting the interface between the αC helix and glycine-rich loop [20,21].…”

Section: Introductionmentioning

confidence: 90%

“…The structure-based pharmacophore model with 18 features was built based on the crystal structure of CK2α in complexed with compound 15 (compound number used in reference [19], PDB code: 5OTZ) using the "Interaction Generation" protocol in Discovery Studio 4.0. In order to optimize the pharmacophore model, ten active compounds reported in the literature were employed to hook the key pharmacophoric features as the positive set, and eight inactive compounds were used as the negative one [18,19] ( Figure S1a). Two hydrophobic features (HY22 and HY39) were recognized by all the ten active compounds, and two H-bond (hydrogen-bond) donor features (HBD32 and HBD96) were hooked by eight out of ten active compounds (Figure 2a).…”

Section: Structure-based Pharmacophore Modelingmentioning

confidence: 99%

Identification and Biological Evaluation of CK2 Allosteric Fragments through Structure-Based Virtual Screening

Zhang

et al. 2020

Molecules

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Casein kinase II (CK2) is considered as an attractive cancer therapeutic target, and recent efforts have been made to develop its ATP-competitive inhibitors. However, achieving selectivity with respect to related kinases remains challenging due to the highly conserved ATP-binding pocket of kinases. Allosteric inhibitors, by targeting the much more diversified allosteric site relative to the highly conserved ATP-binding pocket, might be a promising strategy with the enhanced selectivity and reduced toxicity than ATP-competitive inhibitors. The previous studies have highlighted the traditional serendipitousity of discovering allosteric inhibitors owing to the complicate allosteric modulation. In this current study, we identified the novel allosteric inhibitors of CK2α by combing structure-based virtual screening and biological evaluation methods. The structure-based pharmacophore model was built based on the crystal structure of CK2α-compound 15 complex. The ChemBridge fragment library was searched by evaluating the fit values of these molecules with the optimized pharmacophore model, as well as the binding affinity of the CK2α-ligand complexes predicted by Alloscore web server. Six hits forming the holistic interaction mechanism with the αD pocket were retained after pharmacophore- and Alloscore-based screening for biological test. Compound 3 was found to be the most potent non-ATP competitive CK2α inhibitor (IC50 = 13.0 μM) with the anti-proliferative activity on A549 cancer cells (IC50 = 23.1 μM). Our results provide new clues for further development of CK2 allosteric inhibitors as anti-cancer hits.

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“…Although often neglected, the impact on the ADMET properties should also be taken in consideration. In the case of the linker, that usually adds rotatable bonds to the system (Ichihara et al, 2011;De Fusco et al, 2017), this modification can lead to poor PK features, like low permeability (Veber et al, 2002).…”

Section: Linkingmentioning

confidence: 99%

In silico Strategies to Support Fragment-to-Lead Optimization in Drug Discovery

et al. 2020

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A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066

Abstract: Graphical abstract

Cited by 59 publications

References 32 publications

2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 2. Structure-Based Optimization and Investigation of Effects Specific to the Allosteric Mode of Action

2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 2. Structure-Based Optimization and Investigation of Effects Specific to the Allosteric Mode of Action

Identification and Biological Evaluation of CK2 Allosteric Fragments through Structure-Based Virtual Screening

In silico Strategies to Support Fragment-to-Lead Optimization in Drug Discovery

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