Novel non-ATP competitive small molecules targeting the CK2 α/β interface

Abstract

Increased CK2 levels are prevalent in many cancers. Combined with the critical role CK2 plays in many cell-signaling pathways, this makes it a prime target for down regulation to fight tumour growth. Herein, we report a fragment-based approach to inhibiting the interaction between CK2α and CK2β at the α-β interface of the holoenzyme. A fragment, CAM187, with an IC₅₀ of 44 μM and a molecular weight of only 257 gmol^-1 has been identified as the most promising compound. Importantly, the lead fragment only bound at the interface and was not observed in the ATP binding site of the protein when co-crystallised with CK2α. The fragment-like molecules discovered in this study represent unique scaffolds to CK2 inhibition and leave room for further optimisation.

Keywords: CK2; Fragment based drug discovery; Protein-protein interaction.

Graphical abstract

Fig. 1

Three previous inhibitors of the CK2 interface: DRB, W16, and the diazodinaphthalene compound.

Scheme 1

(a) CH₂Cl₂, Py, Tf₂O, (b) ArB(OH)₂, K₂CO₃, DCE, Pd(PPh₃)₄, (c) LiAlH₄, Et₂O, AlCl₃. Full procedures are detailed in the Supporting Information.

Scheme 2

(a) Indole-4-boronic acid, K₃PO₄, PCy₃, Pd₂(dba)₃, 1,4-dioxane, (b) LiAlH₄, AlCl₃, Et₂O.

Fig. 2

A selection of the analogues of NMR154 synthesised. The analogues in the blue box maintained all the features of NMR154 but added additional functionality onto the nitrogen. The red box shows analogues which kept the dichlorobenzene moiety but substituted the methylamine for the groups shown. Finally, the green box shows substitutions made to the chlorine highlighted in green.

Fig. 3

A side-by-side depiction of five fragments binding in the interface site of CK2α. a) NMR154L binds so that the dichloro moiety anchors the fragment into the hydrophobic pocket (pdb: 5CLP). The ethylamino group juts out of the pocket to form an H-bond with Asp37 outside the pocket. b) Compound 3 maintains the H-bond with Asp37. The second aromatic ring provides a better hydrophobic interaction in the pocket as it occupies more of the space. c) Compound 6 shows some promise as an interface binder. The interaction with Asp37 is maintained as well as the biaryl core occupying the width of the pocket. It is clear from the image there is an unoccupied area of the pocket beneath the pyrrole ring. This is a potential area for growth. d) The lead fragment CAM187 (7), like its predecessors, forms an H-bond with Asp37. This time with the aid of a bridging water molecule. In indole moiety provides the best hydrophobic interactions out of the molecules tested. It provides both the with to fill the pocket as well as the depth to fill it.