title: 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1.
abstract: Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2 H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2 H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.
authors.affiliation: KuDOS Pharmaceuticals Ltd., 410 Cambridge Science Park, Milton Road, Cambridge, U.K. kmenear@kudospharma.co.uk
authors.forename: Keith A
authors.initials: KA
authors.lastname: Menear
authors.forename: Claire
authors.initials: C
authors.lastname: Adcock
authors.forename: Robert
authors.initials: R
authors.lastname: Boulter
authors.forename: Xiao-ling
authors.initials: XL
authors.lastname: Cockcroft
authors.forename: Louise
authors.initials: L
authors.lastname: Copsey
authors.forename: Aaron
authors.initials: A
authors.lastname: Cranston
authors.forename: Krystyna J
authors.initials: KJ
authors.lastname: Dillon
authors.forename: Jan
authors.initials: J
authors.lastname: Drzewiecki
authors.forename: Sheila
authors.initials: S
authors.lastname: Garman
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gomez
authors.forename: Hashim
authors.initials: H
authors.lastname: Javaid
authors.forename: Frank
authors.initials: F
authors.lastname: Kerrigan
authors.forename: Charlotte
authors.initials: C
authors.lastname: Knights
authors.forename: Alan
authors.initials: A
authors.lastname: Lau
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Loh
authors.forename: Ian T W
authors.initials: IT
authors.lastname: Matthews
authors.forename: Stephen
authors.initials: S
authors.lastname: Moore
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Smith
authors.forename: Niall M B
authors.initials: NM
authors.lastname: Martin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C532854:4-(3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl)-2H-phthalazin-1-one; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases