INO-1001

INO-1001 is a potent and selective inhibitor of PARP [1].

Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in DNA repair and as a mediator of energy failure-induced cell death and NAD+ depletion [1].

In rodent and human fibroblast cell lines, INO-1001 significantly inhibited PARP activity. Treatment of 10 μM INO-1001 and a single dose of radiation caused significant radiosensitization of the three cells lines. While apoptosis was not increased, suggesting that INO-1001 increased radiation-induced cell killing through interfering with DNA repair mechanisms, increasing necrotic cell death [2].

In adult male mice subjected to moderate controlled cortical impact (CCI), injection intracerebral with INO-1001 (1.6 mg/kg) preserved brain NAD+ levels. In the Morris water maze, INO-1001 reduced the latency time to find the hidden platform and increased the time in the target quadrant [1]. In dogs underwent hypothermic cardiopulmonary bypass, reperfusion for 60 min after treatment with INO-1001 (1 mg/kg), INO-1001 significantly recovered left and right ventricular systolic function, increased coronary blood flow [3].

References:

[1]. Clark RS, Vagni VA, Nathaniel PD, et al. Local administration of the poly(ADP-ribose) polymerase inhibitor INO-1001 prevents NAD+ depletion and improves water maze performance after traumatic brain injury in mice. J Neurotrauma, 2007, 24(8): 1399-1405.

[2]. Szabó G, Soós P, Mandera S, et al. INO-1001 a novel poly(ADP-ribose) polymerase (PARP) inhibitor improves cardiac and pulmonary function after crystalloid cardioplegia and extracorporal circulation. Shock, 2004, 21(5): 426-432.

[3]. Brock WA, Milas L, Bergh S, et al. Radiosensitization of human and rodent cell lines by INO-1001, a novel inhibitor of poly(ADP-ribose) polymerase. Cancer Lett, 2004, 205(2): 155-160.

A phase IB trial of intravenous INO-1001 plus oral temozolomide in subjects with unresectable stage-III or IV melanoma.[Pubmed:19440934]

Cancer Invest. 2009 Aug;27(7):756-63.

INO-1001 is a PARP-1 inhibitor that interrupts the repair process of N-methylpurines generated by temozolomide. We evaluated the pharmacokinetics of INO-1001 and determined its safety when used with temozolomide at 200 mg/m(2)/day x 5 days every 4 weeks. We enrolled 12 adult patients, in cohorts of 3-6 patients, into the study. INO-1001 at doses of 100, 200 and 400 mg was given intravenous for 1 hr q 12 hr for 10 doses. INO-1001 had a moderate clearance, volume of distribution and a relatively short terminal half-life. Myelosuppression and elevation of liver transaminases were dose-limiting toxicities (DLTs) of INO-1001 at 400 mg.

Local administration of the poly(ADP-ribose) polymerase inhibitor INO-1001 prevents NAD+ depletion and improves water maze performance after traumatic brain injury in mice.[Pubmed:17711401]

J Neurotrauma. 2007 Aug;24(8):1399-405.

Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme best known for its role in DNA repair and as a mediator of NAD+ depletion and energy failure-induced cell death. We tested the effect of the potent and selective ideno-isoquinolone PARP-1 inhibitor INO-1001 after controlled cortical impact (CCI) in mice. Anesthetized adult male mice were subjected to moderate CCI (velocity 6 m/sec, depth 1.2 mm) or sham-injury. Immediately after CCI or sham-injury mice received either INO-1001 (1.6 mg/kg) or vehicle via intracerebral injection (5 microl over 5 min) in a randomized fashion. At 2 h, contused brain tissue was dissected and NAD+ levels were measured. Separate mice underwent neuropathological outcome tests that included spatial memory acquisition (Morris water maze days 14-20), and assessment of contusion volume and hippocampal cell death at day 21. Local treatment with INO-1001 preserved brain NAD+ levels 2 h after CCI (vehicle = 67 +/- 7.6, INO-1001 = 95.8 +/- 4.4 % uninjured hemisphere; n = 6/group, p = 0.03). In the Morris water maze, treatment with INO-1001 reduced the latency to find the hidden platform and increased the time spent in the target quadrant versus vehicle after CCI (n = 11/group, p < or = 0.05). Histological damage did not differ between vehicle and INO-1001-treated mice after CCI. Treatment with INO-1001 prevented NAD+ depletion and improved outcome, although modestly, identifying PARP-mediated energy failure as a contributor to the pathological sequelae of TBI. Further study testing the effects of PARP inhibitors is warranted, specifically in models of brain injury where energy failure is seen.

Therapeutic injection of PARP inhibitor INO-1001 preserves cardiac function in porcine myocardial ischemia and reperfusion without reducing infarct size.[Pubmed:20395771]

Shock. 2010 May;33(5):507-12.

Pharmacological protection from myocardial reperfusion injury, despite plenty of approaches, has still not been realized in humans. We studied the putative infarct size (IS)-sparing capacity of poly(ADP-ribose)polymerase inhibitor, INO-1001, and focused on cardiac functional recovery during reperfusion. Male farm-bred Landrace pigs were subjected to 1-h left anterior descending coronary artery occlusion followed by 3 h of reperfusion (control). Infarct size was determined by triphenyltetrazolium chloride/Evans blue staining. Plasma markers of myocardial injury (troponin T, creatine kinase, lactate dehydrogenase) were determined upon protocol completion. Cardiac function was continuously assessed via pulmonary and femoral artery catheters. INO-1001 (1 mg/kg) was administered upon reperfusion in the treatment group. As a positive control, untreated pigs were subjected to ischemic preconditioning (10-min left anterior descending coronary artery occlusion followed by 15-min reperfusion before the intervention). Ischemic preconditioning reduced myocardial damage reflected by a smaller IS and lower plasma markers of myocardial injury. INO-1001 did not reduce IS but significantly improved functional recovery (increased stroke volume, cardiac index, and mixed venous oxygen saturation) during reperfusion compared with vehicle-treated control and ischemic preconditioning. Although we could not confirm the IS-sparing capacities of poly(ADP-ribose)polymerase inhibitor, INO-1001, the drug holds the potential of hemodynamic improvement during reperfusion.

A randomized, placebo-controlled trial to evaluate the tolerability, safety, pharmacokinetics, and pharmacodynamics of a potent inhibitor of poly(ADP-ribose) polymerase (INO-1001) in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of the TIMI 37 trial.[Pubmed:18535785]

J Thromb Thrombolysis. 2009 May;27(4):359-64.

BACKGROUND: Reperfusion injury is a significant complication of the management of ST-elevation MI (STEMI). INO-1001 is a potent inhibitor of poly(ADP-ribose) polymerase (PARP), a mediator of oxidant-induced myocyte dysfunction during reperfusion. METHODS & RESULTS: We assessed the safety and pharmacokinetics of INO-1001 in a randomized, placebo-controlled, single-blind, dose-escalating trial in 40 patients with STEMI undergoing primary percutaneous coronary intervention within 24 h of onset. INO-1001 was well-tolerated. A trend toward more frequent transaminitis was observed with 800 mg. Plasma from INO1001-treated patients reduced in vitro PARP activity >90% at all doses. Serial C-reactive protein and IL-6 levels showed a trend toward blunting of inflammation with INO-1001. The apparent median terminal half-life (t(1/2)) of INO-1001 was 7.5 (25th, 75th: 5.9, 10.2) h. CONCLUSIONS: The results from this first trial of INO-1001 in STEMI support future investigation of INO-1001 as a novel treatment for reperfusion injury.

Beneficial effects of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase in a rat model of splanchnic artery occlusion and reperfusion.[Pubmed:9249240]

Br J Pharmacol. 1997 Jul;121(6):1065-74.

1. Peroxynitrite, a potent cytotoxic oxidant formed by the reaction of nitric oxide with superoxide anion, and hydroxyl radical, formed in the iron-catalysed Fenton reaction, are important mediators of reperfusion injury. In in vitro studies, DNA single strand breakage, triggered by peroxynitrite or by hydroxyl radical, activates the nuclear enzyme poly (ADP-ribose) synthetase (PARS), with consequent cytotoxic effects. Using 3-aminobenzamide, an inhibitor of PARS, we investigated the role of PARS in the pathogenesis of splanchnic artery occlusion shock. 2. Splanchnic artery occlusion and reperfusion shock (SAO/R) was induced in rats by clamping both the superior mesenteric artery and the coeliac trunk for 45 min, followed by release of the clamp (reperfusion). At 60 min after reperfusion, animals were killed for histological examination and biochemical studies. 3. SAO/R rats developed a significant fall in mean arterial blood pressure, significant increase of tissue myeloperoxidase activity and marked histological injury to the distal ileum. SAO/R was also associated with a significant mortality (0% survival at 2 h after reperfusion). 4. There was a marked increase in the oxidation of dihydrorhodamine 123 to rhodamine (a marker of peroxynitrite-induced oxidative processes) in the plasma of the SAO/R rats, starting early after reperfusion, but not during ischaemia alone. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific 'footprint' of peroxynitrite, in the necrotic ileum in shocked rats, as measured at 60 min after the start of reperfusion. 5. In addition, in ex vivo studies in aortic rings from shocked rats, we found reduced contractions to noradrenaline and reduced responsiveness to a relaxant effect to acetylcholine (vascular hyporeactivity and endothelial dysfunction, respectively). 6. In a separate set of studies, using a 4000 Dalton fluorescent dextran tracer, we investigated the changes in epithelial permeability associated with SAO/R. Ten minutes of reperfusion, after 30 min of splanchnic artery ischaemia, resulted in a marked increase in epithelial permeability. 7. There was a significant increase in PARS activity in the intestinal epithelial cells, as measured 10 min after reperfusion ex vivo. 3-Aminobenzamide, a pharmacological inhibitor of PARS (applied at 10 mg kg(-1), i.v., 5 min before reperfusion, followed by an infusion of 10 mg kg(-1) h(-1)), significantly reduced ischaemia/reperfusion injury in the bowel, as evaluated by histological examination. Also it significantly improved mean arterial blood pressure, improved contractile responsiveness to noradrenaline, enhanced the endothelium-dependent relaxations and reduced the reperfusion-induced increase in epithelial permeability. 8. 3-Aminobenzamide also prevented the infiltration of neutrophils into the reperfused intestine, as evidenced by reduced myeloperoxidase activity. It improved the histological status of the reperfused tissues, reduced the production of peroxynitrite in the late phase of reperfusion and improved survival. 9. In conclusion, our study demonstrates that the PARS inhibitor 3-aminobenzamide exerts multiple protective effects in splanchnic artery occlusion/reperfusion shock. We suggest that peroxynitrite and/or hydroxyl radical, produced during the reperfusion phase, trigger DNA strand breakage, PARS activation and subsequent cellular dysfunction. The vascular endothelium is likely to represent an important cellular site of protection by 3-aminobenzamide in SAO shock.

3-Aminobenzamide protects cells from UV-B-induced apoptosis by acting on cytoskeleton and substrate adhesion.[Pubmed:7864864]

Biochem Biophys Res Commun. 1995 Feb 15;207(2):715-24.

3-aminobenzamide (3-ABA) is an inhibitor of poly-(ADP-ribose)-polymerase, an enzyme involved in numerous subcellular processes, including cell death. Recently, a target effect of the drug on some cytoskeletal elements has also been described (Malorni et al., Biochem. Biophys. Res. Commun. 202: 915-922, 1994). In this study we evaluated the ability of 3-ABA to interfere with UV-B ray-induced apoptosis in cells selected for their cytoskeletal features and their different capability to adhere to the substrate. Human melanoma (M14) and epithelial (A431) cell lines and murine primary fibroblastic cultures (MFC) were studied. Our results indicate that cytoskeleton is indeed an important cellular target of 3-ABA, which can prevent apoptotic cell death by UV-B through a specific effect on the adhesion properties of the cells. Indeed, an inverse correlation was observed between sensitivity to UV-B-induced apoptosis (M14 > A431 > MFC) and substrate adhesion (MFC > A431 > M14). The potential relevance of these observations to understand the possible relationships among apoptosis, cytoskeletal functions and substrate adhesion is discussed.

3-Aminobenzamide (PARP-IN-1) is a potent inhibitor of PARP with IC50 of appr 50 nM in CHO cells, and acts as a mediator of oxidant-induced myocyte dysfunction during reperfusion.

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