DDR THERAPEUTIC APPROACH

Cells are the building blocks of life.

The life cycle of a cell involves distinct phases of growth, DNA replication and cell division.

Atrin’s work focuses on the replication stage of the cell cycle.

DNA Damage Response (DDR)

Cells are continuously exposed to endogenous and exogenous stress that can lead to DNA damage.  To counter this lethal threat, cells have several mechanisms to detect DNA damage, activate the appropriate repair pathway or, if irreparable, induce cell cycle arrest or apoptosis. These DDR processes are vital for cell survival.

Cancer cells rely on various alternative DNA damage response pathways, to repair and resist DNA damage and replication stress.  Several genes, including ATM, ATR, and PARP1/2, are involved in the pathway and are mutated in many cancers. An approach to treating tumors deficient in DNA Damage Response pathway has been to exploit the potential for synthetic lethality, using potent, small-molecule inhibitors of PARP1/2. Targeting DNA Damage Repair, several commercially-available PARP inhibitors induced substantial objective response in patients with DNA repair defects, and received FDA Breakthrough Designation for several cancer indications.  The notable commercial success of these PARP inhibitors has made DNA Damage and Response a clinically- and commercially-validated therapeutic approach.

 

The Role of ATR in DNA Damage Response

 

Ataxia Telangiectasia and Rad3-related (ATR) and Checkpoint Kinase 1 (CHK1) are critical DNA damage response kinases that stabilize stalled replication forks and prevent their collapse into DNA double strand breaks (DSBs). ATR is one of several key proteins that regulate a cell’s response to damaged DNA that results during cell division.  DNA damage comes in two primary forms, as DNA double-strand breaks (DSBs) or DNA single-strand breaks (SSBs), that result from a variety of chemical, UV and other insults. ATR regulates responses to DNA replication abnormalities and functions as a checkpoint kinase upstream of CHK1.

 

Large scale genomic studies identified ATR as one of the top six frequently-altered DNA damage response genes in aggressive cancers. Targeting ATR increases sensitivity to treatment with chemotherapy, radiation therapy and PARP inhibitors, making this approach particularly attractive for development of novel combinatorial therapies. Inhibition of the ATR-CHK1 pathway is synthetically lethal with multiple cancer-associated changes, including oncogenic stress and defects in the DNA damage response pathway.

 

ATRIN’s DNA Damage and Response Approach and Products

 

Targeting ATR represents an emerging strategy to treat a broad spectrum of cancers, most notably those that currently lack fully effective treatments. The scientific founders of Atrin were the first to identify ATR as a good target for cancer therapy. The specificity of ATR inhibitors is vital to their successful clinical application, as off-targeting effects outside of ATR is believed to substantially increase toxicity to normal cells.  There are currently three ATR-inhibitors in Phase I/II clinical trials, developed by Merck KGaA, AstraZeneca and Bayer.

 

Atrin’s development pipeline is based on products resulting from a rationally designed series of novel conformationally restricted macrocyclic molecules, which:

  • Have the highest known potency for inhibiting ATR, and

  • Exhibit what Atrin believes to be best-in-class ATR selectivity with minimal inhibitory activity towards other PIK-related kinases.

 

Atrin believes that comparative preclinical data indicates that its lead compound, ATRN-119, has significant potential to become the best-in-class ATR inhibitor.  ATRN-119 appears to have potency, specificity, and (in some cases) route of administration advantages over other clinical-stage ATRi.

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