title: The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models.
abstract: 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.
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Lenka
authors.initials: L
authors.lastname: Oplustil O'Connor
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, United Kingdom.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Rulten
authors.affiliation: KuDOS Pharmaceuticals Ltd, Cambridge, United Kingdom.
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Cranston
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Odedra
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Henry
authors.initials: H
authors.lastname: Brown
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Janneke E
authors.initials: JE
authors.lastname: Jaspers
authors.affiliation: KuDOS Pharmaceuticals Ltd, Cambridge, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: Jones
authors.affiliation: KuDOS Pharmaceuticals Ltd, Cambridge, United Kingdom.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Knights
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Evers
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Attilla
authors.initials: A
authors.lastname: Ting
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bradbury
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Marina
authors.initials: M
authors.lastname: Pajic
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Sven
authors.initials: S
authors.lastname: Rottenberg
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Rudge
authors.affiliation: KuDOS Pharmaceuticals Ltd, Cambridge, United Kingdom.
authors.forename: Niall M B
authors.initials: NM
authors.lastname: Martin
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, United Kingdom.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Caldecott
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Lau
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, United Kingdom. mark.j.oconnor@astrazeneca.com.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D055808:Drug Discovery; D019398:Genes, BRCA1; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D010879:Piperazines / Q000008:administration & dosage; D010880:Piperidines / Q000494:pharmacology* / Q000633:toxicity; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000502:physiology*; D051381:Rats; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C000609611:AZD2461; D010793:Phthalazines; D010879:Piperazines; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003606:Dacarbazine; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse; C531550:olaparib; D000077204:Temozolomide