Ataxia telangiectasia and Rad3-related (ATR) kinase protects genome integrity during DNA replication. RP-3500 is a novel, orally bioavailable clinical-stage ATR kinase inhibitor (NCT04497116). RP-3500 is highly potent with IC 50 values of 1.0 and 0.33 nM in biochemical and cell-based assays, respectively. RP-3500 is highly selective for ATR with 30-fold selectivity over mTOR and >2,000-fold selectivity over ATM, DNA-PK, and PI3Kkinases. In vivo, RP-3500 treatment results in potent single-agent efficacy and/or tumor regression in multiple xenograft models at minimum effective doses (MED) of 5-7 mg/kg once daily. Pharmacodynamic assessments validate target engagement, with dose-proportional tumor pCHK1 inhibition (IC 80 = 18.6 nM) and induction of -H2AX, pDNA-PKcs, and pKAP1. RP-3500 exposure at MED indicates that circulating free plasma levels above the in vivo tumor IC 80 for 10-12 hours are sufficient for efficacy on a continuous schedule. However, short-duration intermittent (weekly 3 days on/4 days off) dosing schedules as monotherapy or given concomitantly with reduced doses of olaparib or niraparib, maximize tumor growth inhibition while minimizing the impact on red blood cell depletion, emphasizing the reversible nature of erythroid toxicity with RP-3500 and demonstrating superior efficacy compared with sequential treatment. These results provide a strong preclinical rationale to support ongoing clinical investigation of the novel ATR inhibitor, RP-3500, on an intermittent schedule as a monotherapy and in combination with PARP inhibitors as a potential means of maximizing clinical benefit.
The HCV NS5B RNA dependent RNA polymerase plays an essential role in viral replication. The discovery of a novel class of inhibitors based on an N,N-disubstituted phenylalanine scaffold and structure-activity relationships studies to improve potency are described.
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