__smbhome.uscs.susx.ac.uk_sf356_Desktop_Oplustil O'Connor et al_AZD2461_Cancer Research_Final_15 Dec 2015.pdf (537.91 kB)
The PARP inhibitor AZD2461 provides insights into the role of PARP3 inhibition for both synthetic lethality and tolerability with chemotherapy in preclinical models
journal contribution
posted on 2023-06-21, 06:02 authored by Stuart Rulten, Keith CaldecottKeith CaldecottThe PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein,so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability.
Funding
Characterisation of the Role of the PARP-3 During DNA Double-Strand Break Repair; G0261; CANCER RESEARCH UK; C6563/A13078
History
Publication status
- Published
File Version
- Accepted version
Journal
Cancer ResearchISSN
0008-5472Publisher
American Association for Cancer ResearchExternal DOI
Issue
20Volume
76Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2017-12-20First Open Access (FOA) Date
2017-12-20First Compliant Deposit (FCD) Date
2017-12-20Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC