RP-6685, a highly potent and selective inhibitor of DNA polymerase theta (Polθ), manifests remarkable oral activity. With an IC 50 value of 5.8 nM in the PicoGreen assay, RP-6685 effectively hinders the enzymatic activity of Polθ. In addition, it demonstrates significant antitumor efficacy as observed in a mouse tumor xenograft model [1].

RP-6685 is extremely potent with an IC 50 of 550 pM against the pol activity of full-length Polθ whereas inactive on the ATPase activity [1]. RP-6685 inhibits Polθ in HEK293 LIG4 -/- cellswith an IC 50 of 0.94 μM [1].

Administering RP-6685 at a dosage of 80 mg/kg orally twice a day for 21 days demonstrated significant antitumor activity in BRCA2-deficient HCT116 mouse models. Despite inducing tumor regression within the first 8 days of treatment in BRCA2 -/- HCT116 models, it proved ineffective in BRCA2 +/+ HCT116 tumors. In another assessment using CD1 mice weighing 20-30 g, a single dose of either 2.5 mg/kg intravenously or orally was tested, yielding pharmacokinetic parameters of clearance (CL) at 36.8 mL/min/kg, a steady-state volume of distribution (V dss) at 1.1 L/kg, a half-life (t 1/2) of 0.4 hours, and a bioavailability (F) of 66%.