Targeting ATR in patients with cancer

Ngoi, Natalie Y. L.; Pilié, Patrick G.; McGrail, Daniel J.; Zimmermann, Michal; Schlacher, Katharina; Yap, Timothy A.

doi:10.1038/s41571-024-00863-5

Cited by 16 publications

(4 citation statements)

References 170 publications

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“…Given the pivotal role of ATR in addressing replication-associated DNA lesions, ATRis emerge as prime candidates for combination therapies incorporating DNA-damaging agents in preclinical and clinical settings . To confirm the synergistic effect of AD1058 combined with PARPi, 30 mg/kg of the approved PARP inhibitor Niraparib alone or plus 50 mg/kg AD1058 were administered to the Granta-519 xenograft model.…”

Section: Results and Discussionmentioning

confidence: 99%

“…Additionally, brain metastases and central nervous system (CNS) involvement have been observed in numerous ATR-related cancers, particularly in mantle cell lymphoma (MCL) with CNS involvement, as well as in brain metastases from ovarian, pancreatic, colonic, and prostate cancers. − These malignancies progress rapidly, and patients often exhibit short-term survival. Therefore, there remains an urgent need for novel ATRis that possess improved physicochemical properties, pharmacokinetic (PK) profiles, safety profiles, target selectivity, brain penetration capacity, and robust bioactivity both in vitro and in vivo. , …”

Section: Introductionmentioning

confidence: 99%

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Discovery of Preclinical Candidate AD1058 as a Highly Potent, Selective, and Brain-Penetrant ATR Inhibitor for the Treatment of Advanced Malignancies

Liu,

Jiang,

Liu

et al. 2024

J. Med. Chem.

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The ataxia telangiectasia-mutated and Rad3-related protein (ATR) plays a crucial role in regulating the cellular DNA-damage response (DDR), making it a promising target for antitumor drug development through synthetic lethality. In this study, we present the discovery and detailed characterization of AD1058, a highly potent and selective ATR inhibitor, with good preclinical pharmacokinetic profiles. AD1058 exhibits superior efficacy in inhibiting cell proliferation, disrupting the cell cycle, and inducing apoptosis compared to AZD6738. AD1058 displays potent antitumor effects as a single agent or in combination with clinically approved tumor therapies such as PARP inhibitors, ionizing radiotherapy, or chemotherapy in vivo. Considering its enhanced ability to permeate the blood−brain barrier, AD1058 is a promising clinical candidate for the treatment of brain metastases and leptomeningeal metastases in solid tumors. Additionally, among reported ATR inhibitors, AD1058 features the shortest synthesis route and the highest efficiency to date.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of Preclinical Candidate AD1058 as a Highly Potent, Selective, and Brain-Penetrant ATR Inhibitor for the Treatment of Advanced Malignancies

Liu,

Jiang,

Liu

et al. 2024

J. Med. Chem.

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“… 742 Ataxia telangiectasia and Rad3-related protein (ATR), an essential regulator of the cellular replication stress response, is involved in cell-cycle arrest, inhibiting the beginning of replication origins, regulating global fork speed, and promoting fork stabilization. 743 ATM and ATR respond to DNA damage by phosphorylating hundreds of substrates. 744 The checkpoint kinase 1 (CHK1) and checkpoint kinase 2 (CHK2) are the major substrates downstream of ATR and ATM, respectively, and are responsible for downregulating the activity of CDKs, thereby preventing cell cycle progression under stress.…”

Section: Classification Of Tumor Biomarkersmentioning

confidence: 99%

Tumor biomarkers for diagnosis, prognosis and targeted therapy

Zhou,

Tao,

Qiu

et al. 2024

Sig Transduct Target Ther

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Tumor biomarkers, the substances which are produced by tumors or the body’s responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.

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“…In a clinical trial, the combination of ATRi and PARPi showed efficacy in HR-deficient, PARPi-resistant, high-grade serous ovarian cancer (HGSOC) patients ( 97 ). Several ATRis are being tested in clinical trials ( 98 ), providing opportunities to overcome PARPi resistance in the near future.…”

Section: Combination Therapies To Overcome Parpi Resistancementioning

confidence: 99%