Targeting DNA repair for treatment of prostate cancer
|Karolinska institutet - Institutionen för medicinsk biokemi och biofysik
|Funding from Vinnova
|SEK 5 000 000
|October 2010 - October 2013
Purpose and goal
In Sweden approximately 10 000 men are diagnosed with prostate cancer each year. Prostate cancer seems to be dependent on homology recombination (HR) to survive. ATR (ATM and Rad3 related) is playing a central role in replication associated DNA damage repair in HR. In this application we wanted to identify and optimize ATR inhibitors and to investigate the observed cancer cell death in preclinical models. We have established a cell based ATR activity screening assay, performed a screen and identified and optimized potent ATR inhibitors.
Results and expected effects
A cellbased ATR activity screen was established, a number of hits identified and further optimized for potency and ADME properties, resulting in two chemical series. The ATR inhibitors (ATRi) reduce cell survival in prostate cancer cells, with less effect on normal cells. Underlying mechanisms has been investigated. We found that some of our ATRi was not completely selective for ATR. Interestingly, a combination of ATR inhibition and inhibition of an additional DDR target significantly improved the efficacy of the compounds, indicating a synergistic effect of the two targets.
Approach and implementation
In collaboration with a screening platform at Karolinska insitute (LCBKI), we have optimised the screening assay and performed a screen. Our medicinal chemists have optimized the compounds into potent ATR inhibitors (ATRi). The effects of the ATRi have been investigated in cellbased as well as molecular biology assays, both individually and in combination with existing chemotherapy. The project team has consisted of medicinal chemists, pharmacologists and biologists. Project meetings have been held on a regular basis.