ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models.
OBJECTIVE
To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888.


METHODS
In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation.


RESULTS
ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K(i)s of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d x 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity.


CONCLUSIONS
ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.
Donawho
Cherrie K
CK
Abbott Laboratories, Abbott Park, Illinois 60064-6074, USA.
Luo
Yan
Y
Luo
Yanping
Y
Penning
Thomas D
TD
Bauch
Joy L
JL
Bouska
Jennifer J
JJ
Bontcheva-Diaz
Velitchka D
VD
Cox
Bryan F
BF
DeWeese
Theodore L
TL
Dillehay
Larry E
LE
Ferguson
Debra C
DC
Ghoreishi-Haack
Nayereh S
NS
Grimm
David R
DR
Guan
Ran
R
Han
Edward K
EK
Holley-Shanks
Rhonda R
RR
Hristov
Boris
B
Idler
Kenneth B
KB
Jarvis
Ken
K
Johnson
Eric F
EF
Kleinberg
Lawrence R
LR
Klinghofer
Vered
V
Lasko
Loren M
LM
Liu
Xuesong
X
Marsh
Kennan C
KC
McGonigal
Thomas P
TP
Meulbroek
Jonathan A
JA
Olson
Amanda M
AM
Palma
Joann P
JP
Rodriguez
Luis E
LE
Shi
Yan
Y
Stavropoulos
Jason A
JA
Tsurutani
Alan C
AC
Zhu
Gui-Dong
GD
Rosenberg
Saul H
SH
Giranda
Vincent L
VL
Frost
David J
DJ
D000284:Administration, Oral; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D004195:Disease Models, Animal; D004285:Dogs; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000188:drug therapy*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib