4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1

Menear, Keith A.; Adcock, Claire; Boulter, Robert; Cockcroft, Xiao-ling; Copsey, Louise; Cranston, Aaron; Dillon, Krystyna J.; Drzewiecki, Jan; Garman, Sheila; Gomez, Sylvie; Javaid, Hashim; Kerrigan, Frank; Knights, Charlotte; Lau, Alan; Loh, Vincent M.; T. W. Matthews, Ian; Moore, Stephen; O’Connor, Mark J.; C. M. Smith, Graeme; M. B. Martin, Niall

doi:10.1021/jm8001263.s001

jm8001263_si_001.pdf (1.73 MB)

4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1

journal contribution

posted on 2008-10-23, 00:00 authored by Keith A. Menear, Claire Adcock, Robert Boulter, Xiao-ling Cockcroft, Louise Copsey, Aaron Cranston, Krystyna J. Dillon, Jan Drzewiecki, Sheila Garman, Sylvie Gomez, Hashim Javaid, Frank Kerrigan, Charlotte Knights, Alan Lau, Vincent M. Loh, Ian T. W. Matthews, Stephen Moore, Mark J. O’Connor, Graeme C. M. Smith, Niall M. B. Martin

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-2H-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]-2H-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.