ATR Targeting

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DNA Damage Response (DDR)

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)

Tuvusertib (formerly M1774) is an investigational, orally administered, selective ATR inhibitor. ATR inhibition is thought to exacerbate oncogenic stress and promote cancer cell death.^5,7

DDRiver Solid Tumors 301⁷ (NCT04170153)

A Phase 1, open-label trial evaluating M1774 in patients with locally advanced or metastatic unresectable solid tumors.

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DDRiver

Are you interested in learning more about a clinical trial program investigating the potential anticancer effect of inhibiting the DDR pathway?

Learn about DDRiver clinical trials

Learn more about DDR

Merck has a focus on pioneering research into the multiple pathways involved in DDR. Inhibiting these pathways can help disrupt the tumor’s ability to repair damage and can restore sensitivity to treatments. Our active areas of research include:

The inhibition of DNA-PK, ATR, and ATM enzymes to prevent them from coordinating DNA repair, thereby irreparably driving cell death

Is the DDR pathway a viable target for cancer therapy? This video discusses the key protein kinases implicated in DDR pathways and the potential implications of inhibition of these pathways in cancer.

Watch video

Other targets under investigation

ATM

This investigational compound has not been approved by any health authority. Safety and efficacy have not been established.

ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia RAD3-related; DDR, DNA damage response; RPA, replication protein A.

Cimprich KA, Cortez D. ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol. 2008;9(8):616-627.
Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev. 2012;26(12):1268-1286.
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.
Zeman MK, Cimprich KA. Causes and consequences of replication stress. Nat Cell Biol. 2014;16(1):2-9.
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.
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.
M1774 in partcipants with metastatic or locally advanced unresectable solid tumors (DDRiver Solid Tumors 301). ClinicalTrials.gov identifier: NCT04170153. Updated November 8, 2023. Accessed December 1, 2023. https://clinicaltrials.gov/ct2/show/NCT04170153

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ATR Targeting

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DDRiver Solid Tumors 301⁷ (NCT04170153)