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- W3204453900 abstract "Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1–DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1–DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro." @default.
- W3204453900 created "2021-10-11" @default.
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- W3204453900 date "2021-09-27" @default.
- W3204453900 modified "2023-10-15" @default.
- W3204453900 title "Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-<i>N</i>-methylpyridine-2-carboxamide (AZD5305): A PARP1–DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs" @default.
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- W3204453900 doi "https://doi.org/10.1021/acs.jmedchem.1c01012" @default.
- W3204453900 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34570508" @default.
- W3204453900 hasPublicationYear "2021" @default.
- W3204453900 type Work @default.