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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

DOI: 10.1021/acs.jmedchem.1c01012 DOI Help

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

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: September 2021
Diamond Proposal Number(s): 14631 , 17180 , 20015

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.

Journal Keywords: Genetics; Assays; Inhibitors; Solubility; Selectivity

Diamond Keywords: Breast Cancer

Subject Areas: Chemistry, Medicine, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 28/09/2021 08:25

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Cancer Drug Discovery Non-Communicable Diseases Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)