Related Experiment Video
Updated: May 17, 2026
MR Molecular Imaging of Prostate Cancer with a Small Molecular CLT1 Peptide Targeted Contrast Agent
Published on: September 3, 2013
Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer
Kelly Coffey1, Timothy J Blackburn, Susan Cook
1Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom.
Abstract:
Tip60 (KAT5) is a histone acetyltransferase (HAT enzyme) involved in multiple cellular processes including transcriptional regulation, DNA damage repair and cell signalling. In prostate cancer, aggressive cases over-express Tip60 which functions as an androgen receptor co-activator via direct acetylation of lysine residues within the KLKK motif of the receptor hinge region. The purpose of this study was to identify and characterise a Tip60 acetylase inhibitor. High-throughput screening revealed an isothiazole that inhibited both Tip60 and p300 HAT activity. This substance (initially identified as 4-methyl-5-bromoisothiazole) and other isothiazoles were synthesised and assayed against Tip60. Although an authentic sample of 4-methyl-5-bromoisothiazole was inactive against Tip60, in an in vitro HAT assay, 1,2-bis(isothiazol-5-yl)disulfane (NU9056) was identified as a relatively potent inhibitor (IC(50) 2 µM). Cellular activity was confirmed by analysis of acetylation of histone and non-histone proteins in a prostate cancer cell line model. NU9056 treatment inhibited cellular proliferation in a panel of prostate cancer cell lines (50% growth inhibition, 8-27 µM) and induced apoptosis via activation of caspase 3 and caspase 9 in a concentration- and time-dependent manner. Also, decreased androgen receptor, prostate specific antigen, p53 and p21 protein levels were demonstrated in response to treatment with NU9056. Furthermore, pre-treatment with NU9056 inhibited both ATM phosphorylation and Tip60 stabilization in response to ionising radiation. Based on the activity of NU9056 and the specificity of the compound towards Tip60 relative to other HAT enzymes, these chemical biology studies have identified Tip60 as a potential therapeutic target for the treatment of prostate cancer.
Insights
Researchers identified NU9056, a potent Tip60 inhibitor, demonstrating its potential as a therapeutic target for prostate cancer by reducing cancer cell proliferation and inducing apoptosis.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Tip60 (KAT5) is a histone acetyltransferase (HAT) enzyme crucial for transcriptional regulation, DNA repair, and cell signaling.
- Aggressive prostate cancers overexpress Tip60, which acts as an androgen receptor co-activator through direct acetylation.
Purpose of the Study:
- To identify and characterize an inhibitor of Tip60 acetylase activity.
- To evaluate the therapeutic potential of Tip60 inhibition in prostate cancer models.
Main Methods:
- High-throughput screening identified isothiazoles as potential HAT inhibitors.
- Synthesis and in vitro HAT assays were performed to identify potent Tip60 inhibitors, leading to the discovery of NU9056.
- Cellular assays assessed the impact of NU9056 on histone/non-histone acetylation, proliferation, apoptosis, and key protein levels in prostate cancer cells.
Main Results:
- NU9056 was identified as a potent Tip60 inhibitor (IC50 = 2 µM) with cellular activity.
- NU9056 inhibited prostate cancer cell proliferation (50% growth inhibition at 8-27 µM) and induced apoptosis.
- Treatment with NU9056 decreased levels of androgen receptor, prostate specific antigen, p53, and p21, and inhibited radiation-induced ATM phosphorylation and Tip60 stabilization.
Conclusions:
- Tip60 is a potential therapeutic target for prostate cancer treatment.
- NU9056 exhibits specific activity against Tip60, supporting its role in chemical biology studies for prostate cancer therapy.
