2. Academic Validation
  3. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1

4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1

  • J Med Chem. 2008 Oct 23;51(20):6581-91. doi: 10.1021/jm8001263.
Keith A Menear 1,  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 Jr,  Ian T W Matthews,  Stephen Moore,  Mark J O'Connor,  Graeme C M Smith,  Niall M B Martin
Affiliations

Affiliation

  • 1 KuDOS Pharmaceuticals Ltd., 410 Cambridge Science Park, Milton Road, Cambridge, U.K. [email protected]
PMID: 18800822 DOI: 10.1021/jm8001263
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.

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