title: Discovery of AZ0108, an orally bioavailable phthalazinone PARP inhibitor that blocks centrosome clustering.
abstract: The propensity for cancer cells to accumulate additional centrosomes relative to normal cells could be exploited for therapeutic benefit in oncology. Following literature reports that suggested TNKS1 (tankyrase 1) and PARP16 may be involved with spindle structure and function and may play a role in suppressing multi-polar spindle formation in cells with supernumerary centrosomes, we initiated a phenotypic screen to look for small molecule poly (ADP-ribose) polymerase (PARP) enzyme family inhibitors that could produce a multi-polar spindle phenotype via declustering of centrosomes. Screening of AstraZeneca's collection of phthalazinone PARP inhibitors in HeLa cells using high-content screening techniques identified several compounds that produced a multi-polar spindle phenotype at low nanomolar concentrations. Characterization of these compounds across a broad panel of PARP family enzyme assays indicated that they had activity against several PARP family enzymes, including PARP1, 2, 3, 5a, 5b, and 6. Further optimization of these initial hits for improved declustering potency, solubility, permeability, and oral bioavailability resulted in AZ0108, a PARP1, 2, 6 inhibitor that potently inhibits centrosome clustering and is suitable for in vivo efficacy and tolerability studies.
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Johannes
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Lynsie
authors.initials: L
authors.lastname: Almeida
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Daly
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Ferguson
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Shaun E
authors.initials: SE
authors.lastname: Grosskurth
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Huiping
authors.initials: H
authors.lastname: Guan
authors.affiliation: AstraZeneca R&D Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Tina
authors.initials: T
authors.lastname: Howard
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Stephanos
authors.initials: S
authors.lastname: Ioannidis
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Kazmirski
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Lamb
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Larsen
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lyne
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Keith
authors.initials: K
authors.lastname: Mikule
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Claude
authors.initials: C
authors.lastname: Ogoe
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Peng
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Philip
authors.initials: P
authors.lastname: Petteruti
authors.affiliation: AstraZeneca R&D Building 310, Milton Science Park, Cambridge CB4 0WG, United Kingdom.
authors.forename: Jon A
authors.initials: JA
authors.lastname: Read
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Nancy
authors.initials: N
authors.lastname: Su
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Sylvester
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Throner
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Wenxian
authors.initials: W
authors.lastname: Wang
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Jiaquan
authors.initials: J
authors.lastname: Wu
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zheng
authors.affiliation: AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006801:Humans; D008861:Microsomes / Q000378:metabolism; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D010793:Phthalazines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051381:Rats; D038501:Tankyrases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D038501:Tankyrases; C000610147:AZ0108; C418109:TNKS protein, human
keywords: Cell cycle; Centrosome; Oncology; PARP; Tankyrase