Targeting IκappaB kinases for cancer therapy

Abstract

The inhibitory kappa B kinases (IKKs) and IKK related kinases are crucial regulators of the pro-inflammatory transcription factor, nuclear factor kappa B (NF-κB). The dysregulation in the activities of these kinases has been reported in several cancer types. These kinases are known to regulate survival, proliferation, invasion, angiogenesis, and metastasis of cancer cells. Thus, IKK and IKK related kinases have emerged as an attractive target for the development of cancer therapeutics. Several IKK inhibitors have been developed, few of which have advanced to the clinic. These inhibitors target IKK either directly or indirectly by modulating the activities of other signaling molecules. Some inhibitors suppress IKK activity by disrupting the protein-protein interaction in the IKK complex. The inhibition of IKK has also been shown to enhance the efficacy of conventional chemotherapeutic agents. Because IKK and NF-κB are the key components of innate immunity, suppressing IKK is associated with the risk of immune suppression. Furthermore, IKK inhibitors may hit other signaling molecules and thus may produce off-target effects. Recent studies suggest that multiple cytoplasmic and nuclear proteins distinct from NF-κB and inhibitory κB are also substrates of IKK. In this review, we discuss the utility of IKK inhibitors for cancer therapy. The limitations associated with the intervention of IKK are also discussed.

Keywords: Cancer therapy; IKK inhibitor; IKK related kinase; Inhibitory kappa B kinase; Nuclear factor kappa B.

Fig. 1

Common pathways of NF-κB activation.

Fig. 2

Common IKK inhibitors studied in cancer models. Abbreviations: AGRO100: G-quadruplexoligodeoxynucleotide; BMS-345541: N-(1,8-Dimethylimidazo[1,2-a]quinoxalin-4-yl)-1,2-ethanediamine; Compound A: fluoromethyl-2,2-difluoro-1-[trifluoromethyl]vinylether; CHS828: 2-[6-(4-chlorophenoxy)hexyl]-1-cyano-3-pyridin-4-ylguanidine; CYL-19s: α-methylenegamma-butyrolactone derivatives; CYT387: N-(cyanomethyl)-4-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl] benzamide; E7: human papillomavirus; IMD-0354: N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide; LCY-2-CHO: 9-(2-chlorobenzyl)-9H-carbazole-3-carbaldehyde; LF15-0195: 2-[6-(diaminomethylideneamino)hexylamino]-2-oxoethyl] N-[4-[[(3R)-3-aminobutyl]amino]butyl]carbamate; MC160: Molluscum contagiosum 160; ML120B: N-(6-chloro-7-methoxy-9H-pyrido[3,4-b]indol-8-yl)-2-methylpyridine-3-carboxamide; NBD peptide: NEMO-binding domain peptide; NS5B: nonstructural protein 5B; PS-1145: N-(6-Chloro-9H-pyrido[3,4-b]indol-8-yl)-3-pyridinecarboxamide; PTEN: phosphatase and tensin homolog; SC-514: 3-Amino-5-thiophen-3-ylthiophene-2-carboxamide; TTV: torque teno virus; vIRF3: viral interferon regulatory factor 3.

Fig. 3

Chemical structure of common IKK inhibitors.

Fig. 3

Chemical structure of common IKK inhibitors.

Fig. 3

Chemical structure of common IKK inhibitors.

Fig. 3

Chemical structure of common IKK inhibitors.