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DOI: 10.1021/acs.jmedchem.1c01012
OpenAccess: Closed
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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

Jeffrey W. Johannes,Amber Balazs,Derek Barratt,Michal Bista,Matthew D. Chuba,Sabina Cosulich,Susan E. Critchlow,Sébastien L. Degorce,Paolo Di Fruscia,Scott D. Edmondson,Kevin J. Embrey,Stephen E. Fawell,Avipsa Ghosh,Sonja J. Gill,Anders Gunnarsson,Sudhir M. Hande,Tom D. Heightman,Paul Hemsley,Giuditta Illuzzi,Jordan Lane,Carrie Larner,Elisabetta Leo,Lina Liu,Andrew Madin,Scott Martin,Lisa McWilliams,Mark J. O’Connor,Jonathan P. Orme,Fiona Pachl,Martin J. Packer,Xiaohui Pei,Andrew Pike,M. Schimpl,Hongyao She,Anna D. Staniszewska,Verity Talbot,E. Underwood,Jeffrey Varnes,Xue Lin,Tieguang Yao,Ke Zhang,Andrew X. Zhang,Xiaolan Zheng

PARP1
Poly ADP ribose polymerase
Chemistry
2021
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.
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    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” is a paper by Jeffrey W. Johannes Amber Balazs Derek Barratt Michal Bista Matthew D. Chuba Sabina Cosulich Susan E. Critchlow Sébastien L. Degorce Paolo Di Fruscia Scott D. Edmondson Kevin J. Embrey Stephen E. Fawell Avipsa Ghosh Sonja J. Gill Anders Gunnarsson Sudhir M. Hande Tom D. Heightman Paul Hemsley Giuditta Illuzzi Jordan Lane Carrie Larner Elisabetta Leo Lina Liu Andrew Madin Scott Martin Lisa McWilliams Mark J. O’Connor Jonathan P. Orme Fiona Pachl Martin J. Packer Xiaohui Pei Andrew Pike M. Schimpl Hongyao She Anna D. Staniszewska Verity Talbot E. Underwood Jeffrey Varnes Xue Lin Tieguang Yao Ke Zhang Andrew X. Zhang Xiaolan Zheng published in 2021. It has an Open Access status of “closed”. You can read and download a PDF Full Text of this paper here.