PMID- 34911817 OWN - NLM STAT- MEDLINE DCOM- 20220307 LR - 20230106 IS - 1538-8514 (Electronic) IS - 1535-7163 (Print) IS - 1535-7163 (Linking) VI - 21 IP - 2 DP - 2022 Feb TI - RP-3500: A Novel, Potent, and Selective ATR Inhibitor that is Effective in Preclinical Models as a Monotherapy and in Combination with PARP Inhibitors. PG - 245-256 LID - 10.1158/1535-7163.MCT-21-0615 [doi] AB - 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 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 (PI3Kalpha) 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) (IC(80) = 18.6 nmol/L) and induction of phosphorylated H2A.X variant histone (gammaH2AX), 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 IC(80) 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. CI - (c)2021 The Authors; Published by the American Association for Cancer Research. FAU - Roulston, Anne AU - Roulston A AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. aroulston@reparerx.com. FAU - Zimmermann, Michal AU - Zimmermann M AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Papp, Robert AU - Papp R AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Skeldon, Alexander AU - Skeldon A AD - Ventus Therapeutics Inc. Saint-Laurent, Quebec, Canada. FAU - Pellerin, Charles AU - Pellerin C AD - Ventus Therapeutics Inc. Saint-Laurent, Quebec, Canada. FAU - Dumas-Berube, Emilie AU - Dumas-Berube E AD - Ventus Therapeutics Inc. Saint-Laurent, Quebec, Canada. FAU - Dumais, Valerie AU - Dumais V AD - Ventus Therapeutics Inc. Saint-Laurent, Quebec, Canada. FAU - Dorich, Stephane AU - Dorich S AUID- ORCID: 0000-0003-4240-9659 AD - Ventus Therapeutics Inc. Saint-Laurent, Quebec, Canada. FAU - Fader, Lee D AU - Fader LD AD - Ventus Therapeutics Inc. Saint-Laurent, Quebec, Canada. FAU - Fournier, Sara AU - Fournier S AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Li, Li AU - Li L AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Leclaire, Marie-Eve AU - Leclaire ME AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Yin, Shou Yun AU - Yin SY AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Chefson, Amandine AU - Chefson A AD - Ventus Therapeutics Inc. Saint-Laurent, Quebec, Canada. FAU - Alam, Hunain AU - Alam H AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Yang, William AU - Yang W AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Fugere-Desjardins, Chloe AU - Fugere-Desjardins C AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Vignini-Hammond, Sabrina AU - Vignini-Hammond S AD - NuChem Sciences Inc. Saint-Laurent, Quebec, Canada. FAU - Skorey, Kathryn AU - Skorey K AD - NuChem Sciences Inc. Saint-Laurent, Quebec, Canada. FAU - Mulani, Amina AU - Mulani A AD - NuChem Sciences Inc. Saint-Laurent, Quebec, Canada. FAU - Rimkunas, Victoria AU - Rimkunas V AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Veloso, Artur AU - Veloso A AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Hamel, Martine AU - Hamel M AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Stocco, Rino AU - Stocco R AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Mamane, Yael AU - Mamane Y AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Li, Zuomei AU - Li Z AD - NuChem Sciences Inc. Saint-Laurent, Quebec, Canada. FAU - Young, Jordan T F AU - Young JTF AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Zinda, Michael AU - Zinda M AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. FAU - Black, W Cameron AU - Black WC AUID- ORCID: 0000-0002-5305-899X AD - Repare Therapeutics Inc., Saint-Laurent, Quebec, Canada. LA - eng PT - Comment PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211215 PL - United States TA - Mol Cancer Ther JT - Molecular cancer therapeutics JID - 101132535 RN - 0 (Poly(ADP-ribose) Polymerase Inhibitors) RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.11.1 (ATR protein, human) RN - EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins) RN - EC 2.7.11.1 (DNA-Activated Protein Kinase) SB - IM CON - Mol Cancer Ther. 2022 Feb;21(2):243. PMID: 35135870 MH - *Ataxia Telangiectasia MH - Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors MH - DNA-Activated Protein Kinase/metabolism MH - Humans MH - *Poly(ADP-ribose) Polymerase Inhibitors/pharmacology/therapeutic use MH - Protein Kinase Inhibitors/pharmacology/therapeutic use PMC - PMC9398170 EDAT- 2021/12/17 06:00 MHDA- 2022/03/08 06:00 PMCR- 2022/08/23 CRDT- 2021/12/16 05:52 PHST- 2021/07/19 00:00 [received] PHST- 2021/10/14 00:00 [revised] PHST- 2021/12/10 00:00 [accepted] PHST- 2021/12/17 06:00 [pubmed] PHST- 2022/03/08 06:00 [medline] PHST- 2021/12/16 05:52 [entrez] PHST- 2022/08/23 00:00 [pmc-release] AID - 1535-7163.MCT-21-0615 [pii] AID - MCT-21-0615 [pii] AID - 10.1158/1535-7163.MCT-21-0615 [doi] PST - ppublish SO - Mol Cancer Ther. 2022 Feb;21(2):245-256. doi: 10.1158/1535-7163.MCT-21-0615. Epub 2021 Dec 15.