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DNA DAMAGE RESPONSE

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

Description and Potential Mechanism of Action:

ATM activity is dispensable for cellular viability, yet necessary for maintaining genome integrity. It plays a pivotal role in DNA double-strand break signaling and repair.3-5

M4076 is an investigational, orally administered, selective, ATP-competitive ATM inhibitor. It is designed to block ATM activity in cells leading to increased double-strand DNA breaks that cannot be repaired and drives tumor cell death.6

DDRi_MoA-Final layouts 3_11_21_Full_

Areas of Interest:

  • Solid tumors

TRIALS

DDRiver Solid Tumors 4107 (NCT04882917)

A Phase I, open-label trial evaluating M4076 in patients with advanced solid tumors.

TARGETS UNDER INVESTIGATION

ATR

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DNA-PK

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DDRiver

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

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VIEWPOINTS ON CANCER

Viewpoints In Cancer

Explore what's next in oncology with insights and perspectives.

EMD Serono is the healthcare business of Merck KGaA, Darmstadt, Germany in the U.S. and Canada.

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

Abbreviations:
ATM, ataxia telangiectasia mutated; ATP, adenosine triphosphate; ATR, ataxia telangiectasia RAD3-related; CHK, checkpoint kinase; DNA-PK, DNA-dependent protein kinase.

References:

  1. Macheret M, Halazonetis TD. DNA replication stress as a hallmark of cancer. Annu Rev Pathol. 2015;10:425-448.
  2. Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer. 2003;3(3):155-168.
  3. 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.
  4. Carrassa L, Damia G. DNA damage response inhibitors: mechanisms and potential applications in cancer therapy. Cancer Treat Rev. 2017;60:139-151.
  5. Goldstein M, Kastan MB. The DNA damage response: implications for tumor responses to radiation and chemotherapy. Annu Rev Med. 2015;66:8.1-8.15.
  6. Fuchss T, Grädler U, Schiemann K, et al. Highly potent and selective ATM kinase inhibitor M4076: a clinical candidate drug with strong anti-tumor activity in combination therapies. Poster presented at: American Association of Cancer Research Annual Meeting; March 29-April 3, 2019; Atlanta, Georgia, USA. Abstract 3500.
  7. First-in-human study of M4076 in advanced solid tumors (DDRiver Solid Tumors 410). ClinicalTrials.gov identifier: NCT04882917. Updated January 12, 2023. Accessed April 28, 2023. https://clinicaltrials.gov/ct2/show/NCT04882917

© 2023 Merck KGaA, Darmstadt, Germany and/or its affiliates. All rights reserved. EMD Serono, Inc. is the healthcare business of Merck KGaA, Darmstadt, Germany in the US and Canada.

US-MULO-00051
Last updated 07/2023

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