ATR targeting

ATR is thought to be activated in response to DNA damage, such as double-strand breaks and replication stress. In cancer, a loss of ATM-p53 signaling is common and leads to dependence of tumor cells on ATR to survive DNA damage.1-3

Replication stress results in sections of exposed single-stranded DNA. Replication Protein A (RPA) binds to and protects single-stranded DNA. Accumulation of RPA results in activation of the ATR pathway, which regulates cell cycle progression and promotes fork repair.4,5

Tuvusertib (ATR inhibitor)

Description and Potential Mechanism of Action:

Tuvusertib (formerly M1774) is an orally administered, selective ATR inhibitor. ATR inhibition is thought to exacerbate oncogenic stress and promote cell death.5,6

Tuvusertib is designed to block ATR activity in cells leading to increased double-strand DNA breaks that cannot be repaired and driving tumor cell death.5-7


Areas of Interest:

  • Solid tumors


DDRiver Solid Tumors 3018 (NCT04170153)

A Phase I, open-label trial evaluating M1774 in patients with locally advanced or metastatic unresectable solid tumors.



Investigational compounds are not approved by any health authority. Safety and efficacy have not been established.

ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia RAD3-related; CDC25A, cell division cycle 25 A; CHK, checkpoint kinase; DNA-PK, DNA-dependent protein kinase.


  1. Cimprich KA, Cortez D. ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol. 2008;9(8):616-627.
  2. Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev. 2012;26:1268-1286.
  3. Hall AB, Newsome D, Wang Y, et al. Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970. Oncotarget. 2014;5(14):5674-5685.
  4. Zeman MK, Cimprich KA. Causes and consequences of replication stress. Nat Cell Biol. 2014;16(1):2-9.
  5. Blackford AN, Jackson SP. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol Cell. 2017;66:801-817.
  6. Yap TA, Tolcher AW, Plummer ER, et al. A first-in-human phase I study of ATR inhibitor M1774 in patients with solid tumors. J Clin Oncol. 2021;39(suppl 15):TPS3153. doi:10.1200/JCO.2021.39.15_suppl.TPS315
  7. Carrassa L, Damia G. DNA damage response inhibitors: mechanisms and potential applications in cancer therapy. Cancer Treat Rev. 2017;60:139-151.
  8. M1774 in participants with metastatic or locally advanced unresectable solid tumors (DDRiver Solid Tumors 301). ClinicalTrials.gov identifier: NCT04170153. Updated April 28, 2022. Accessed April 28, 2023. https://www.clinicaltrials.gov/ct2/show/NCT04170153