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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
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:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Chemistry
Structural biology
Organic Chemistry
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)