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HTS discovery of PARP1-HPF1 complex inhibitors in cancer
Timothy Kellett1, Rida Noor2, Qiong Zhou3
1Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus (CU AMC), Aurora, CO, USA.
Abstract:
PARP1/2 inhibitors (PARPi) are effective clinically used drugs for the treatment of cancers with BRCA deficiencies. PARPi have had limited success and applicability beyond BRCA deficient cancers, and their effect is diminished by resistance mechanisms. The recent discovery of Histone PARylation Factor (HPF1) and the role it plays in the PARylation reaction by forming a shared active site with PARP1 raises the possibility that novel inhibitors that target the PARP1-HPF1 complex can be identified. Herein we describe a simple and cost-effective high-throughput screening (HTS) method aimed at discovering inhibitors of the PARP1-HPF1 complex. Upon HTS validation, we first applied this method to screen a small PARP-focused library of compounds and then scale up our approach using robotic automation to conduct a pilot screen of 10,000 compounds and validating >100 hits. This work demonstrates for the first time the capacity to discover potent inhibitors of the PARP1-HPF1 complex, which may have utility as probes to better understand the DNA damage response and as therapeutics for cancer.
Insights
Researchers developed a new high-throughput screening method to discover inhibitors targeting the PARP1-Histone PARylation Factor (HPF1) complex. This approach may lead to novel cancer therapeutics beyond BRCA-deficient cancers.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective for BRCA-deficient cancers but have limited applicability and efficacy in other cancers due to resistance mechanisms.
- The discovery of Histone PARylation Factor (HPF1) and its role in forming a shared active site with PARP1 presents a new target for drug development.
Purpose of the Study:
- To develop a simple, cost-effective high-throughput screening (HTS) method for identifying inhibitors of the PARP1-HPF1 complex.
- To demonstrate the utility of this HTS method for discovering novel PARP1-HPF1 complex inhibitors.
Main Methods:
- Development and validation of a high-throughput screening (HTS) assay for the PARP1-HPF1 complex.
- Screening of a focused PARP library followed by robotic automation for a pilot screen of 10,000 compounds.
Main Results:
- Successfully developed and validated a novel HTS method for the PARP1-HPF1 complex.
- Identified over 100 validated hits from a pilot screen of 10,000 compounds, demonstrating the method's capacity to discover potent inhibitors.
Conclusions:
- This work presents the first successful discovery of potent inhibitors targeting the PARP1-HPF1 complex.
- These novel inhibitors could serve as research tools for understanding DNA damage response and as potential therapeutics for various cancers.
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