4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1.
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.
Menear
Keith A
KA
KuDOS Pharmaceuticals Ltd., 410 Cambridge Science Park, Milton Road, Cambridge, U.K. kmenear@kudospharma.co.uk
Adcock
Claire
C
Boulter
Robert
R
Cockcroft
Xiao-ling
XL
Copsey
Louise
L
Cranston
Aaron
A
Dillon
Krystyna J
KJ
Drzewiecki
Jan
J
Garman
Sheila
S
Gomez
Sylvie
S
Javaid
Hashim
H
Kerrigan
Frank
F
Knights
Charlotte
C
Lau
Alan
A
Loh
Vincent M
VM
Matthews
Ian T W
IT
Moore
Stephen
S
O'Connor
Mark J
MJ
Smith
Graeme C M
GC
Martin
Niall M B
NM
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
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