RP-3500: A Novel, Potent, and Selective ATR Inhibitor that is Effective in Preclinical Models as a Monotherapy and in Combination with PARP Inhibitors
Ataxia telangiectasia and Rad3-related (ATR) kinase plays a critical role in safeguarding genome integrity during DNA replication. RP-3500, an orally bioavailable ATR kinase inhibitor currently in clinical development (NCT04497116), exhibits potent activity with IC50 values of 1.0 nmol/L in biochemical assays and 0.33 nmol/L in cell-based assays. RP-3500 demonstrates high selectivity for ATR, with 30-fold specificity over mammalian target of rapamycin (mTOR) and more than 2,000-fold specificity over other kinases, including ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and phosphatidylinositol 3-kinase alpha (PI3Kα).
In vivo, RP-3500 delivers robust single-agent efficacy and tumor regression across multiple xenograft models at minimum effective doses (MED) of 5 to 7 mg/kg administered once daily. Pharmacodynamic evaluations confirm target engagement, showing dose-dependent inhibition of phosphorylated checkpoint kinase 1 (pCHK1) (IC80 = 18.6 nmol/L) and increased levels of phosphorylated H2A.X variant histone (γH2AX), phosphorylated DNA-PK catalytic subunit (pDNA-PKcs), and phosphorylated KRAB-associated protein 1 (pKAP1).
RP-3500 achieves efficacy with circulating free plasma concentrations exceeding the in vivo tumor IC80 for 10–12 hours on a continuous dosing schedule. Notably, intermittent dosing schedules (three days on, four days off weekly) as monotherapy or in combination with reduced doses of olaparib or niraparib optimize tumor growth inhibition while minimizing erythroid toxicity. This intermittent regimen highlights the reversible nature of red blood cell depletion associated with RP-3500 and achieves superior efficacy compared to sequential treatment.
These findings provide a compelling preclinical rationale for the continued clinical investigation of RP-3500, both as a standalone therapy and in combination with PARP inhibitors,VB124 using an intermittent dosing strategy to maximize therapeutic benefits.