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| Ref Type | Journal Article | ||||||||||||
| PMID | (34911817) | ||||||||||||
| Authors | Roulston A, Zimmermann M, Papp R, Skeldon A, Pellerin C, Dumas-Bérube É, Dumais V, Dorich S, Fader LD, Fournier S, Li L, Leclaire ME, Yin SY, Chefson A, Alam H, Yang W, Fugère-Desjardins C, Vignini-Hammond S, Skorey K, Mulani A, Rimkunas V, Veloso A, Hamel M, Stocco R, Mamane Y, Li Z, Young JTF, Zinda M, Black WC | ||||||||||||
| Title | RP-3500: A Novel, Potent, and Selective ATR Inhibitor that is Effective in Preclinical Models as a Monotherapy and in Combination with PARP Inhibitors. | ||||||||||||
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| Abstract Text | 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. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
|---|
| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
|---|---|---|---|---|
| RP-3500 | RP 3500|RP3500|Camonsertib | ATR Inhibitor 16 | RP-3500 binds to and inhibits ATR, which may lead to decreased downstream signaling and inhibition of tumor growth (PMID: 34911817). |
| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|---|---|---|---|---|
| ATM | A2843V | missense | unknown | ATM A2843V lies within the PI3K/PI4K domain of the Atm protein (UniProt.org). A2843V has been identified in the scientific literature (PMID: 34911817), but has not been biochemically characterized and therefore, its effect on Atm protein function is unknown (PubMed, Oct 2024). | |
| ATM | Q1919P | missense | unknown | ATM Q1919P does not lie within any known functional domains of the Atm protein (UniProt.org). Q1919P has been identified in the scientific literature (PMID: 34911817), but has not been biochemically characterized and therefore, its effect on Atm protein function is unknown (PubMed, Oct 2024). |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| ATM Q628Pfs*7 ATM I1581Nfs*5 ATM A2843V | colon adenocarcinoma | sensitive | RP-3500 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, RP-3500 inhibited viability in a colon adenocarcinoma cell line harboring ATM Q628Pfs*7, ATM I1581Nfs*5, and ATM A2843V in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 34911817). | 34911817 |
| ATM loss | stomach cancer | sensitive | RP-3500 | Preclinical - Pdx | Actionable | In a preclinical study, RP-3500 resulted in complete tumor regression in a gastric cancer patient-derived xenograft (PDX) model with biallelic loss of ATM (PMID: 34911817). | 34911817 |
| ATM R2832C | mantle cell lymphoma | sensitive | Niraparib + RP-3500 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of RP-3500 with Zejula (niraparib) inhibited tumor growth in a mantle cell lymphoma cell line xenograft model harboring ATM R2832C (PMID: 34911817). | 34911817 |
| ATM R2832C | mantle cell lymphoma | sensitive | RP-3500 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, RP-3500 inhibited viability in a mantle cell lymphoma cell line harboring ATM R2832C in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 34911817). | 34911817 |
| ATM Q1919P | lung non-small cell carcinoma | sensitive | RP-3500 | Preclinical - Cell culture | Actionable | In a preclinical study, RP-3500 inhibited viability in a non-small cell lung cancer cell line harboring ATM Q1919P in culture (PMID: 34911817). | 34911817 |