Camonsertib

Camonsertib (RP-3500) is an orally active, selective ATR kinase inhibitor (ATRi) with an IC 50 of 1.00 nM in biochemical assays. Camonsertib shows 30-fold selectivity for ATR over mTOR (IC 50 =120 nM) and >2,000-fold selectivity over ATM , DNA-PK , and PI3Kα kinases. Camonsertib has potent antitumor activity In Vitro Camonsertib (RP-3500; 1 μM; 1-24 hours) inhibits CHK1(Ser345) phosphorylation from 1 to 3 hours. ? Camonsertib inhibits Gemcitabine stimulated ATR phosphorylation of its substrate pCHK1(Ser345) with an IC 50 of 0.33 nM in a LoVo cell-based assay. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Western Blot AnalysisCell Line: LoVo and CW-2 human colon cancer cell lines Concentration: 1 μM Incubation Time: 1, 2, 4, 6, 8, 16, 24 hours Result: Inhibited CHK1(Ser345) phosphorylation from 1 to 3 hours. Starting at 4 hours, CHK1(Ser345) became re-phosphorylated as DNA-PKcs became activated in treated cells, along with its substrates KAP1 and H2AX. In Vivo Camonsertib (RP-3500; 3, 7, 15 mg/kg; Orally; once daily for 18 days) produces dose-dependent tumor growth inhibition with a minimum effective dose (MED) of 7 mg/kg in LoVo xenografts . ? Camonsertib (5, 10 mg/kg; Orally; once daily) produces statistically significant tumor growth inhibition in the CW-2 colon xenograft model . ? Camonsertib (7 mg/kg; for 7 days) results in 8.1- and 2.7-fold inductions of KAP1 and DNA-PKcs phosphorylation in mice bearing LoVo tumors . ? Camonsertib has a more profound anti-tumor effect occurred at higher doses on the 3 days on/4 days off (30 mg/kg) and 5 days on/2 days off (25 mg/kg) schedules compared with consecutive daily administrations (10 mg/kg) at a lower dose for 14 days . ? Camonsertib (15mg/kg) combined PARPi Olaparib (80mg/kg; both agents days 1-3 on/4 days off) or sequential (PARPi for 3 days followed by RP-3500 for 3 days then 1 day off) schedules produces greater antiTumor effects compared with sequential administration without affecting tolerability . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Female mice (6-8 weeks old) bearing LoVo xenografts Dosage: 3, 7, 15 mg/kg (0.5% methylcellulose/0.02% SDS vehicle) Administration: Orally; once daily for 18 days Result: Produced dose-dependent tumor growth inhibition with a minimum effective dose (MED) of 7 mg/kg. The maximum tolerated dose (MTD) was 10 mg/kg once daily on a continuous dosing schedule. Form:Solid IC50& Target:ATR ATM >30 μM (IC 50 ) mTOR 120 nM (IC 50 )

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