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RBN012759 is a potent, selective and orally active inhibitor of PARP14, with an IC50 of <3 nM. RBN012759 displays 300-fold selectivity over the monoPARPs and 1000-fold selectivity over the polyPARPs. RBN012759 decreases pro-tumor macrophage function and elicits inflammatory responses in tumor explants[1].

RBN012759 (0.01-10 μM) decreases the MAR/PAR signal corresponding to PARP14 self MARylation and stabilizes PARP14 protein in a dose-dependent manner in human primary macrophages[1].RBN012759 (0.1-10 μM) reduces IL-4 stimulated cytokine secretion in human primary macrophages[1].

RBN012759 (500 mg/kg BID; p.o.) is well-tolerated in mice with repeat dosing[1].RBN012759 (100 mg/kg; p.o.) exhibits moderate orally bioavailability (30%) and short plasma half-life (0.4 h) due to moderate clearance (54 mL/min/kg) and low steady-state volume of distribution (1.4 L/kg) in mice[1].

[1]. Schenkel L, et, al. A potent and selective PARP14 inhibitor decreases pro-tumor macrophage function and elicits inflammatory responses in tumor explants. AACR Annual Meeting 2020.

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