Targeting Casein Kinase 2 and Histone Deacetylase with a Dual Inhibitor Effectively Reduces Tumor Growth in a
Irene Ortín1, Laura Ochoa-Callejero2,3, Christian Werner4
1Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte 28668, Spain.
Abstract:
In a previous study, IOR-160 was identified as a potent dual inhibitor of CK2 and HDAC enzymes. In this study, we evaluated its selectivity and therapeutic potential. IOR-160 exhibited high selectivity for CK2 within a panel of 21 kinases and more widespread inhibitory activity against histone deacetylases (HDAC 1, 2, 3, and 6, low activity for HDAC8). Using a mouse model of triple-negative breast cancer (MDA-MB-231), we further explored its effects on disease progression. Notably, animals treated with IOR-160 exhibited no detectable signs of toxicity or behavioral side effects relative to untreated mice. In a xenograft study, IOR-160 significantly reduced tumor growth (p = 0.0336) and decreased tumor burden (p = 0.0454) compared to the vehicle (DMSO)-treated group. In addition, IOR-160 modulated critical cellular signaling pathways, demonstrated by the inhibition of AKT phosphorylation (p = 0.0175) and a significant increase in acetylated α-tubulin (p = 0.0023), confirming the dual action of IOR-160 in vivo. Furthermore, X-ray crystallography revealed the binding mode of IOR-160 to CK2, showing high conservation compared to that of the known CK2 inhibitor CX-4945. These results suggest that IOR-160 has significant potential as an antitumor agent. Nonclinical and clinical studies become now necessary to validate the efficacy of this new chemical entity as a potential drug.
Insights
IOR-160 is a dual inhibitor of CK2 and HDAC enzymes with potential as an antitumor agent. This compound showed high selectivity, reduced tumor growth in mice, and no significant toxicity, warranting further clinical investigation.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- IOR-160 identified as a dual inhibitor of Casein Kinase 2 (CK2) and Histone Deacetylase (HDAC) enzymes.
- Previous studies established IOR-160 as a potent inhibitor, necessitating further evaluation of its therapeutic potential and selectivity.
Purpose of the Study:
- To evaluate the selectivity profile of IOR-160 against a panel of kinases and HDAC enzymes.
- To assess the therapeutic efficacy and safety of IOR-160 in a mouse model of triple-negative breast cancer (MDA-MB-231).
- To elucidate the molecular mechanisms underlying IOR-160's antitumor activity in vivo.
Main Methods:
- Kinase and HDAC inhibition assays to determine selectivity.
- Xenograft mouse model of triple-negative breast cancer (MDA-MB-231) for efficacy studies.
- Analysis of signaling pathway modulation (AKT phosphorylation, acetylated α-tubulin) and X-ray crystallography for binding mode determination.
Main Results:
- IOR-160 demonstrated high selectivity for CK2 and broad activity against HDACs (1, 2, 3, 6).
- Treatment with IOR-160 significantly reduced tumor growth and burden in MDA-MB-231 xenografts with no observable toxicity.
- In vivo studies confirmed dual inhibition through decreased AKT phosphorylation and increased acetylated α-tubulin, consistent with CK2 and HDAC inhibition.
Conclusions:
- IOR-160 exhibits significant antitumor potential as a dual CK2 and HDAC inhibitor.
- The compound's high selectivity, efficacy in preclinical models, and favorable safety profile support its advancement.
- Further nonclinical and clinical studies are required to validate IOR-160 as a potential therapeutic agent for cancer treatment.
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