ATM Targeting

DNA Damage Response (DDR)

ATM targeting

ATM mutations occur frequently in cancer cells. Inherited ATM deficiency leads to ataxia–telangiectasia, a genome instability syndrome characterized by neurodegeneration, immunodeficiency, radiation sensitivity, and cancer susceptibility. Thus, ATM has a clear role in the maintenance of genome stability, cellular and tissue functioning, and cancer prevention.^1,2

Upon detection of a double-stranded break (DSB), ATM is recruited to the break site. Following activation, ATM triggers a signaling cascade resulting in cell cycle arrest and DSB repair. It can also trigger apoptosis or senescence if necessary.^3-5

M4076

M4076 is an investigational, orally administered, selective ATP-competitive ATM inhibitor. ATM activity is dispensable for cellular viability, yet necessary for maintaining genome integrity. It plays a pivotal role in DNA DSB signaling and repair.^3-5

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

ATR

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; DSB, double-stranded break.

Macheret M, Halazonetis TD. DNA replication stress as a hallmark of cancer. Annu Rev Pathol. 2015;10:425-448.
Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer. 2003;3(3):155-168.
Blackford AN, Jackson SP. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol Cell. 2017;66(6):801-817.
Carrassa L, Damia G. DNA damage response inhibitors: mechanisms and potential applications in cancer therapy. Cancer Treat Rev. 2017;60:139-151.
Goldstein M, Kastan MB. The DNA damage response: implications for tumor responses to radiation and chemotherapy. Annu Rev Med. 2015;66:129-143

GL-MULO-00159 | December 2023

GL-MULO-00232 | December 2025

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ATM Targeting

DNA Damage Response (DDR)

ATM targeting

M4076

Abbreviations

References

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