The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models
| العنوان: | The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models |
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| المؤلفون: | Niall M. B. Martin, Bastiaan Evers, Charlotte Knights, Janneke E. Jaspers, Jos Jonkers, Attilla Ting, Henry Brown, Keith W. Caldecott, Sven Rottenberg, Rajesh Odedra, Lenka Oplustil O'Connor, Robert Hugh Bradbury, Aaron Cranston, David Alan Rudge, Mark J. O'Connor, Marina Pajic, Louise J. Jones, Alan Lau, Stuart L. Rulten |
| المصدر: | Cancer Research. 76:6084-6094 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, DNA Repair, medicine.medical_treatment, Genes, BRCA1, Synthetic lethality, Poly(ADP-ribose) Polymerase Inhibitors, Pharmacology, Biology, Q1, Piperazines, Olaparib, Mice, 03 medical and health sciences, chemistry.chemical_compound, Piperidines, Bone Marrow, Cell Line, Tumor, Drug Discovery, Temozolomide, medicine, Animals, Humans, ATP Binding Cassette Transporter, Subfamily B, Member 1, PARP Inhibitor AZD2461, Chemotherapy, Cancer, Neoplasms, Experimental, medicine.disease, Xenograft Model Antitumor Assays, Rats, 3. Good health, Dacarbazine, 030104 developmental biology, medicine.anatomical_structure, Oncology, Tolerability, chemistry, PARP inhibitor, Phthalazines, Bone marrow, Poly(ADP-ribose) Polymerases, DNA Damage |
| الوصف: | The 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. Cancer Res; 76(20); 6084–94. ©2016 AACR. |
| وصف الملف: | application/pdf |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::318c6f6c6cc972443af48c50dbf1283f https://doi.org/10.1158/0008-5472.can-15-3240 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....318c6f6c6cc972443af48c50dbf1283f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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