FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4282974984> ?p ?o ?g. }

• W4282974984 endingPage "6302" @default.
• W4282974984 startingPage "6302" @default.
• W4282974984 abstract "Abstract PARP inhibitors exploit defects in DNA repair pathways to selectively target cancerous cells via PARP1 catalytic inhibition and PARP1 trapping onto the DNA. All known clinical PARP1 inhibitors bind at the same site at the catalytic center of the enzyme. However, despite this resemblance they show immensely different outcomes in terms of response rate in the clinic due to their varying degree of PARP trapping ability. Moreover, the first-generation PARP inhibitors were not optimized for selectivity across the PARP family potentially driving undesirable side effects, including intestinal toxicity from tankyrase inhibition or hematological toxicity from PARP2 inhibition. There has been strong rationale for the use of PARP inhibitors in neuro-oncology. However, the first-generation PARP inhibitors have limited CNS distribution as these drugs were not designed for brain penetration. Recently AstraZeneca has reported the discovery of AZD5305, a next generation PARP1 selective inhibitor and PARP1-DNA trapper which was not designed with a CNS penetrant profile. Given the unmet need of a brain penetrant PARP1 inhibitor, we set out to identify a highly potent and selective PARP1 inhibitor and trapper with CNS profile. In our next generation PARP1 inhibitor, we sought to retain the profile of AZD5305 and lower the efflux for CNS penetration. Despite the challenge of narrow SAR, we successfully used the structure- and property-based design approach to identify a brain penetrant PARP1 inhibitor and PARP1-DNA trapper. We used multiple medicinal chemistry maneuvers such as masking the hydrogen bond donors and core modifications to lower the efflux in order to achieve brain penetration. Further optimization of the nicotinamide mimetic core for potency and metabolic stability led us to the discovery of AZD9574.AZD9574 shows improved selectivity for PARP1 over PARP2 vs AZD5305 and retains its excellent selectivity over other PARP family members. It has low efflux in Caco2, MDCK-MDR1, and MDCK-MDR1-BCRP permeability assays and it also showed CNS penetration in rat and cynomolgus monkey. AZD9574 has excellent secondary pharmacology and acceptable physicochemical properties and good PK in preclinical species.In vitro, AZD9574 selectively inhibits the growth of BRCAm cell lines. Importantly, AZD9574 showed efficacy in an intracranial BRCA1m MDA-MB-436 xenograft model at doses of 3, 10 and 30 mg/kg QD, significantly extending the survival of tumor-bearing mice compared to vehicle control arm.In summary, AZD9574 is a next generation selective PARP1 inhibitor and trapper with CNS penetration. This profile makes it an ideal candidate for treating CNS malignancies or brain metastases that have a dependence on PARP inhibition either as single agent or in combination with other therapies. Citation Format: Avipsa Ghosh, Sudhir M. Hande, Amber Balazs, Derek Barratt, Sabina Cosulich, Barry Davies, Sébastien Degorce, Kevin Embrey, Sonja Gill, Anders Gunnarsson, Giuditta Illuzzi, Peter Johnström, Jordan Lane, Carrie Larner, Rachel Lawrence, Elisabetta Leo, Andrew Madin, Elizabeth Martin, Lisa McWilliams, Lenka O’Connor, Mark O’Connor, Jonathan Orme, Fiona Pachl, Martin Packer, Andy Pike, Philip Rawlins, Marianne Schimpl, Magnus Schou, Anna Staniszewska, Wenzhan Yang, James Yates, Andrew Zhang, XiaoLa Zheng, Stephen Fawell, Petra Hamerlik, Jeffrey Johannes. Structure-based and property-based drug design of AZD9574, a CNS penetrant PARP1 selective inhibitor and trapper [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6302." @default.
• W4282974984 created "2022-06-17" @default.
• W4282974984 creator A5000275517 @default.
• W4282974984 creator A5001137841 @default.
• W4282974984 creator A5002540006 @default.
• W4282974984 creator A5005150760 @default.
• W4282974984 creator A5008032721 @default.
• W4282974984 creator A5008491342 @default.
• W4282974984 creator A5009458077 @default.
• W4282974984 creator A5010517370 @default.
• W4282974984 creator A5011515348 @default.
• W4282974984 creator A5012852116 @default.
• W4282974984 creator A5014206922 @default.
• W4282974984 creator A5016397144 @default.
• W4282974984 creator A5020818396 @default.
• W4282974984 creator A5021132085 @default.
• W4282974984 creator A5026150958 @default.
• W4282974984 creator A5027439140 @default.
• W4282974984 creator A5036255361 @default.
• W4282974984 creator A5036732655 @default.
• W4282974984 creator A5037030469 @default.
• W4282974984 creator A5037190863 @default.
• W4282974984 creator A5047627113 @default.
• W4282974984 creator A5052291594 @default.
• W4282974984 creator A5052571824 @default.
• W4282974984 creator A5053808561 @default.
• W4282974984 creator A5058181236 @default.
• W4282974984 creator A5058717267 @default.
• W4282974984 creator A5059935361 @default.
• W4282974984 creator A5064954724 @default.
• W4282974984 creator A5066191804 @default.
• W4282974984 creator A5068765187 @default.
• W4282974984 creator A5075165775 @default.
• W4282974984 creator A5076395097 @default.
• W4282974984 creator A5078659370 @default.
• W4282974984 creator A5081140523 @default.
• W4282974984 creator A5082455051 @default.
• W4282974984 creator A5091683932 @default.
• W4282974984 date "2022-06-15" @default.
• W4282974984 modified "2023-10-14" @default.
• W4282974984 title "Abstract 6302: Structure-based and property-based drug design of AZD9574, a CNS penetrant PARP1 selective inhibitor and trapper" @default.
• W4282974984 doi "https://doi.org/10.1158/1538-7445.am2022-6302" @default.
• W4282974984 hasPublicationYear "2022" @default.
• W4282974984 type Work @default.
• W4282974984 citedByCount "0" @default.
• W4282974984 crossrefType "journal-article" @default.
• W4282974984 hasAuthorship W4282974984A5000275517 @default.
• W4282974984 hasAuthorship W4282974984A5001137841 @default.
• W4282974984 hasAuthorship W4282974984A5002540006 @default.
• W4282974984 hasAuthorship W4282974984A5005150760 @default.
• W4282974984 hasAuthorship W4282974984A5008032721 @default.
• W4282974984 hasAuthorship W4282974984A5008491342 @default.
• W4282974984 hasAuthorship W4282974984A5009458077 @default.
• W4282974984 hasAuthorship W4282974984A5010517370 @default.
• W4282974984 hasAuthorship W4282974984A5011515348 @default.
• W4282974984 hasAuthorship W4282974984A5012852116 @default.
• W4282974984 hasAuthorship W4282974984A5014206922 @default.
• W4282974984 hasAuthorship W4282974984A5016397144 @default.
• W4282974984 hasAuthorship W4282974984A5020818396 @default.
• W4282974984 hasAuthorship W4282974984A5021132085 @default.
• W4282974984 hasAuthorship W4282974984A5026150958 @default.
• W4282974984 hasAuthorship W4282974984A5027439140 @default.
• W4282974984 hasAuthorship W4282974984A5036255361 @default.
• W4282974984 hasAuthorship W4282974984A5036732655 @default.
• W4282974984 hasAuthorship W4282974984A5037030469 @default.
• W4282974984 hasAuthorship W4282974984A5037190863 @default.
• W4282974984 hasAuthorship W4282974984A5047627113 @default.
• W4282974984 hasAuthorship W4282974984A5052291594 @default.
• W4282974984 hasAuthorship W4282974984A5052571824 @default.
• W4282974984 hasAuthorship W4282974984A5053808561 @default.
• W4282974984 hasAuthorship W4282974984A5058181236 @default.
• W4282974984 hasAuthorship W4282974984A5058717267 @default.
• W4282974984 hasAuthorship W4282974984A5059935361 @default.
• W4282974984 hasAuthorship W4282974984A5064954724 @default.
• W4282974984 hasAuthorship W4282974984A5066191804 @default.
• W4282974984 hasAuthorship W4282974984A5068765187 @default.
• W4282974984 hasAuthorship W4282974984A5075165775 @default.
• W4282974984 hasAuthorship W4282974984A5076395097 @default.
• W4282974984 hasAuthorship W4282974984A5078659370 @default.
• W4282974984 hasAuthorship W4282974984A5081140523 @default.
• W4282974984 hasAuthorship W4282974984A5082455051 @default.
• W4282974984 hasAuthorship W4282974984A5091683932 @default.
• W4282974984 hasConcept C12554922 @default.
• W4282974984 hasConcept C143425029 @default.
• W4282974984 hasConcept C181199279 @default.
• W4282974984 hasConcept C182979987 @default.
• W4282974984 hasConcept C185592680 @default.
• W4282974984 hasConcept C2778480876 @default.
• W4282974984 hasConcept C2779138821 @default.
• W4282974984 hasConcept C502942594 @default.
• W4282974984 hasConcept C552990157 @default.
• W4282974984 hasConcept C55493867 @default.
• W4282974984 hasConcept C82381507 @default.
• W4282974984 hasConcept C86803240 @default.
• W4282974984 hasConcept C98274493 @default.
• W4282974984 hasConceptScore W4282974984C12554922 @default.
• W4282974984 hasConceptScore W4282974984C143425029 @default.
• W4282974984 hasConceptScore W4282974984C181199279 @default.

• next