AI Article Synopsis
- The chromatin-associated ATPases Tip48 and Tip49 are involved in important nuclear processes like DNA repair and gene regulation, often overexpressed in cancers, but their exact role is not well understood.
- Research shows that depleting Tip49 leads to increased apoptosis in a p53-dependent manner and can inhibit the development of leukemia in mouse models.
- A new compound, DS-4950, was created to inhibit the function of Tip48/49, proving to be safe in healthy mice while significantly reducing tumor size and improving survival rates, indicating that these ATPases could be crucial targets for cancer therapy.
Article Abstract
The chromatin-associated AAA+ ATPases Tip48 and Tip49 are the core components of various complexes implicated in diverse nuclear events such as DNA repair and gene regulation. Although they are frequently overexpressed in many human cancers, their functional significance remains unclear. Here, we show that loss of Tip49 triggered p53-dependent apoptosis and inhibited leukemia development in vivo. To examine the impact of chemical inhibition of this complex on leukemia, we have developed the novel compound DS-4950, which interferes with the ATPase activity of the Tip48/49. Administration of DS-4950 was well-tolerated in healthy mice, and the drug effectively reduced tumor burden and improved survival. We also provide evidence that the dependency on Tip48/49 is widely conserved in non-hematologic malignancies with wild type p53. These results demonstrated that the Tip48/49 ATPases are functionally necessary and therapeutically targetable for the treatment of human cancers.
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| http://dx.doi.org/10.1038/s41375-023-01971-4 | DOI Listing |
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