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Blog - ABT-888
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Last Updated January 6, 2008
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As you may recall, this agent is extremely potent and selective for PARP, with high solubility and oral bioavailability, and excellent pharmacokinetics, thus making it ideal for both in vitro and in vivo proof-of-concept studies. For these reasons it is likely to become an industry benchmark.
From earlier:
This material has been well characterized, and its potency against PARP validated to be 5 nM in vitro.
ABT-888 has the following characteristics:
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ABT-888 potently inhibits both PARP-1 and PARP-2.
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Low molecular weight, high solubility and permeability, excellent bioavailability.
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ABT-888 was selected to have minimal CYP 450 inhibition and induction so as to minimize potential for drug-drug interactions.
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Was selected from a large number of related structures. In the process they demonstrated that a 500-1000-fold window between the PARP cellular IC50 and the IC50 for cytotoxicity could be achieved, thus demonstrating that effective PARP inhibitors do not need to have inherent cytotoxicity. Consistent with this ABT-888 has no single agent activity in tumor models. A large therapeutic index (TI) was achieved in mice, and the toxicities of chemotherapeutic agents were not significantly altered. Because the potentiation of DNA-damaging agents is observed over a very broad dose response range, it is believed that clinically they should be able to demonstrate benefits well below toxic doses. The excellent single agent safety may make ABT-888 or one of its similar congeners ideal for chronic use indications.
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In spite of the small size of ABT-888 in the NAD binding pocket, they have looked at numerous other NAD binding enzymes and have observed no inhibition of any other enzymes beside PARP-1 and PARP-2.
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Excellent bioavailability and demonstrated good blood-brain permeation (based upon brain tissue levels, concentrations in CSF, and orthotopic gliomas).
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R-stereoisomer has been selected for clinical development, this enantiomer has advantages over the antipode/racemate with regard to potency, efficacy, therapeutic window, and pharmacokinetics.
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Significantly increased tumor growth delay resulting from radiation and DNA-damaging agents at well-tolerated doses in murine models.
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Clinical Phase 0 evidence (NCI) of extensive inhibition was achieved in PBMCs and tumor biopsies. Good PK/PD correlate. Target plasma levels of 210 nM were exceeded and maintained for up to 12h at 50mg doses with no observed adverse effects.
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Posted by L. Arnold on January 6, 2008
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