DNA DAMAGE RESPONSE

The ATM pathway

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 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, potent, 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

The ATM Pathway

Areas of Interest:

TRIALS

DDRiver Solid Tumors 4107 (NCT04882917)

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

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DDRiver clinical trial program

DDRiver

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Pathways Under Investigation

DNA-PK

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Abbreviations:
ATM, ataxia telangiectasia mutated; ATP, adenosine triphosphate; ATR, ataxia telangiectasia RAD3-related; 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 October 19, 2021. Accessed November 4, 2021. https://clinicaltrials.gov/ct2/show/NCT04882917

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