RP-3500
(Synonyms: RP-3500; ATR inhibitor 4) 目录号 : GC64278
RP-3500 (Camonsertib, ATR inhibitor) is a highly potent and selective inhibitor of ATR kinase with an IC50 of 1 nM.
Cas No.:2417489-10-0
Sample solution is provided at 25 µL, 10mM.
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RP-3500 (Camonsertib, ATR inhibitor) is a highly potent and selective inhibitor of ATR kinase with an IC50 of 1 nM.
[1] Roulston A, et al. Mol Cancer Ther. 2022 Feb;21(2):245-256.
Cas No. | 2417489-10-0 | SDF | Download SDF |
别名 | RP-3500; ATR inhibitor 4 | ||
分子式 | C21H26N6O3 | 分子量 | 410.47 |
溶解度 | 储存条件 | Store at -20°C | |
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1 mg | 5 mg | 10 mg |
1 mM | 2.4362 mL | 12.1812 mL | 24.3623 mL |
5 mM | 0.4872 mL | 2.4362 mL | 4.8725 mL |
10 mM | 0.2436 mL | 1.2181 mL | 2.4362 mL |
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给药剂量 | mg/kg | 动物平均体重 | g | 每只动物给药体积 | ul | 动物数量 | 只 | |||
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RP-3500: A Novel, Potent, and Selective ATR Inhibitor that is Effective in Preclinical Models as a Monotherapy and in Combination with PARP Inhibitors
Mol Cancer Ther 2022 Feb;21(2):245-256.PMID:34911817DOI:10.1158/1535-7163.MCT-21-0615.
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 IC50 values of 1.0 and 0.33 nmol/L in biochemical and cell-based assays, respectively. RP-3500 is highly selective for ATR with 30-fold selectivity over mammalian target of rapamycin (mTOR) and more than 2,000-fold selectivity over ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and phosphatidylinositol 3-kinase alpha (PI3Kα) kinases. 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 to 7 mg/kg once daily. Pharmacodynamic assessments validate target engagement, with dose-proportional tumor inhibition of phosphorylated checkpoint kinase 1 (pCHK1) (IC80 = 18.6 nmol/L) and induction of phosphorylated H2A.X variant histone (γH2AX), phosphorylated DNA-PK catalytic subunit (pDNA-PKcs), and phosphorylated KRAB-associated protein 1 (pKAP1). RP-3500 exposure at MED indicates that circulating free plasma levels above the in vivo tumor IC80 for 10 to 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.
Guiding ATR and PARP inhibitor combinationswith chemogenomic screens
Cell Rep 2022 Jul 12;40(2):111081.PMID:35830811DOI:10.1016/j.celrep.2022.111081.
Combinations of ataxia telangiectasia- and Rad3-related kinase inhibitors (ATRis) and poly(ADP-ribose) polymerase inhibitors (PARPis) synergistically kill tumor cells through modulation of complementary DNA repair pathways, but their tolerability is limited by hematological toxicities. To address this, we performed a genome-wide CRISPR-Cas9 screen to identify genetic alterations that hypersensitize cells to a combination of the ATRi RP-3500 with PARPi, including deficiency in RNase H2, RAD51 paralog mutations, or the "alternative lengthening of telomeres" telomere maintenance mechanism. We show that RP-3500 and PARPi combinations kill cells carrying these genetic alterations at doses sub-therapeutic as single agents. We also demonstrate the mechanism of combination hypersensitivity in RNase H2-deficient cells, where we observe an irreversible replication catastrophe, allowing us to design a highly efficacious and tolerable in vivo dosing schedule. We present a comprehensive dataset to inform development of ATRi and PARPi combinations and an experimental framework applicable to other drug combination strategies.