2. Academic Validation
  3. Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N-methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs

Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N-methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs

  • J Med Chem. 2021 Oct 14;64(19):14498-14512. doi: 10.1021/acs.jmedchem.1c01012.
Jeffrey W Johannes 1,  Amber Balazs 1,  Derek Barratt 2,  Michal Bista 2,  Matthew D Chuba 1,  Sabina Cosulich 3,  Susan E Critchlow 4,  Sébastien L Degorce 1,  Paolo Di Fruscia 2,  Scott D Edmondson 1,  Kevin Embrey 2,  Stephen Fawell 5,  Avipsa Ghosh 1,  Sonja J Gill 6,  Anders Gunnarsson 7,  Sudhir M Hande 1,  Tom D Heightman 8,  Paul Hemsley 2,  Giuditta Illuzzi 4,  Jordan Lane 2,  Carrie Larner 6,  Elisabetta Leo 4,  Lina Liu 9,  Andrew Madin 2,  Scott Martin 10,  Lisa McWilliams 2,  Mark J O'Connor 4,  Jonathan P Orme 2,  Fiona Pachl 11,  Martin J Packer 12,  Xiaohui Pei 9,  Andrew Pike 10,  Marianne Schimpl 2,  Hongyao She 9,  Anna D Staniszewska 4,  Verity Talbot 2,  Elizabeth Underwood 2,  Jeffrey G Varnes 1,  Lin Xue 9,  Tieguang Yao 9,  Ke Zhang 9,  Andrew X Zhang 11,  Xiaolan Zheng 1
Affiliations

Affiliations

  • 1 Chemistry, Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 2 Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 OWG, U.K.
  • 3 Oncology Projects, Oncology R&D, AstraZeneca, Cambridge CB4 OWG, U.K.
  • 4 Bioscience, Oncology R&D, AstraZeneca, Cambridge CB4 OWG, U.K.
  • 5 Oncology Discovery, Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 6 Oncology Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge CB4 OWG, U.K.
  • 7 Discovery Sciences, R&D Gothenburg, AstraZeneca, KJ2, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
  • 8 Chemistry, Oncology R&D, AstraZeneca, Cambridge CB4 OWG, U.K.
  • 9 Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China.
  • 10 DMPK, Oncology R&D, AstraZeneca, Cambridge CB4 OWG, U.K.
  • 11 Discovery Sciences, R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 12 Computational Chemistry, Oncology R&D, AstraZeneca, Cambridge CB4 OWG, U.K.
PMID: 34570508 DOI: 10.1021/acs.jmedchem.1c01012
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-132167
    99.79%, PARP Inhibitor