Inhibiting CK2 in breast cancer: From molecular targets to drug candidates.

Casein kinase 2 (CK2) is a constitutively active serine/threonine kinase that orchestrates multiple oncogenic signaling networks, including PI3K/Akt, NF-κB, JAK/STAT3, Wnt/β-catenin, and DNA damage response pathways. Its broad involvement in cell survival, proliferation, and therapy resistance has positioned CK2 as a compelling target in oncology, particularly in breast cancer where CK2α and CK2β are frequently overexpressed and correlate with poor prognosis. Over the past decades, a wide range of CK2 inhibitors has been developed ranging from classical ATP-competitive scaffolds (TBB, DMAT, CX-4945) to highly selective second-generation chemical probes (SGC-CK2-1, AB668) and substrate-targeting peptides (CIGB-300). While two candidates, CX-4945 and CIGB-300, have advanced to clinical evaluation, major challenges persist, including limited selectivity, suboptimal pharmacokinetics, and reduced in vivo potency. Notably, kinome-wide profiling has revealed that several traditional inhibitors, including CX-4945, display substantial off-target activity, complicating the attribution of cellular phenotypes directly to CK2 inhibition. Emerging strategies including allosteric, αD-pocket-directed, bivalent, and substrate-targeting approaches have substantially improved selectivity and enabled more precise interrogation of CK2 biology. Preclinical evidence highlights strong antitumor effects of CK2 blockade in hormone-refractory and triple-negative breast cancer (TNBC), with additional potential to overcome endocrine and chemoresistance. This review integrates recent advances in CK2 biology, summarizes the evolution of CK2 inhibitor classes, and outlines the opportunities and remaining barriers for translating CK2 inhibition into effective cancer therapeutics.