Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models

Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph A.; Deeg, Gesa; Mumberg, Dominik; Nussbaum, Franz von

doi:10.1021/acs.jmedchem.0c00369

Cited by 49 publications

(27 citation statements)

References 46 publications

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“…ATR inhibitors, such as AZD6738 and VE-821 as well as the CHK1 inhibitor SAR-020106 were effective radiosensitizers in preclinical studies (100)(101)(102). An ongoing phase I clinical trial (NCT03188965) is assessing the safety profile of ATR inhibitors (BAY1895344) (103).…”

Section: Atr-chk1mentioning

confidence: 99%

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

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DNA replication is a process fundamental in all living organisms in which deregulation, known as replication stress, often leads to genomic instability, a hallmark of cancer. Most malignant tumors sustain persistent proliferation and tolerate replication stress via increasing reliance to the replication stress response. So whilst replication stress induces genomic instability and tumorigenesis, the replication stress response exhibits a unique cancer-specific vulnerability that can be targeted to induce catastrophic cell proliferation. Radiation therapy, most used in cancer treatment, induces a plethora of DNA lesions that affect DNA integrity and, in-turn, DNA replication. Owing to radiation dose limitations for specific organs and tumor tissue resistance, the therapeutic window is narrow. Thus, a means to eliminate or reduce tumor radioresistance is urgently needed. Current research trends have highlighted the potential of combining replication stress regulators with radiation therapy to capitalize on the high replication stress of tumors. Here, we review the current body of evidence regarding the role of replication stress in tumor progression and discuss potential means of enhancing tumor radiosensitivity by targeting the replication stress response. We offer new insights into the possibility of combining radiation therapy with replication stress drugs for clinical use.

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Section: Atr-chk1mentioning

confidence: 99%

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

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“…Following these initial studies, several structurally unrelated ATR inhibitors have been described and widely assayed in multiple preclinical models of cancers [ 91 , 92 , 93 , 94 , 95 , 96 ]. Recently, phase I/II cancer clinical trials have been launched to assess the role of ATR inhibitors, either as single agents or in combinations with chemotherapy, radiotherapy, and immunotherapy in patients with advanced and refractory solid tumors (clinicaltrials.gov and [ 97 ]), with the first results reported [ 98 , 99 , 100 , 101 ].…”

Section: Harnessing Replicative Stress As a Cancer Vulnerability In MMmentioning

confidence: 99%

Genomic Instability and Replicative Stress in Multiple Myeloma: The Final Curtain?

Botrugno

Tonon

2021

Cancers

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Multiple Myeloma (MM) is a genetically complex and heterogeneous hematological cancer that remains incurable despite the introduction of novel therapies in the clinic. Sadly, despite efforts spanning several decades, genomic analysis has failed to identify shared genetic aberrations that could be targeted in this disease. Seeking alternative strategies, various efforts have attempted to target and exploit non-oncogene addictions of MM cells, including, for example, proteasome inhibitors. The surprising finding that MM cells present rampant genomic instability has ignited concerted efforts to understand its origin and exploit it for therapeutic purposes. A credible hypothesis, supported by several lines of evidence, suggests that at the root of this phenotype there is intense replicative stress. Here, we review the current understanding of the role of replicative stress in eliciting genomic instability in MM and how MM cells rely on a single protein, Ataxia Telangiectasia-mutated and Rad3-related protein, ATR, to control and survive the ensuing, potentially fatal DNA damage. From this perspective, replicative stress per se represents not only an opportunity for MM cells to increase their evolutionary pool by increasing their genomic heterogeneity, but also a vulnerability that could be leveraged for therapeutic purposes to selectively target MM tumor cells.

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“…BAY 1895344 is another oral selective and potent ATR inhibitor discovered and optimized for in vivo studies using the high-throughput screening of chemical compounds [61]. Preclinical studies of this drug as monotherapy in DDR deficiencies revealed promising antitumor activity as well as synergistic activity in combination with DNA damage-inducing chemotherapy or radiotherapy [62].…”

Section: Atr Inhibitorsmentioning

confidence: 99%

Therapeutic Targeting of DNA Damage Response in Cancer

Choi

Lee

2022

IJMS

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DNA damage response (DDR) is critical to ensure genome stability, and defects in this signaling pathway are highly associated with carcinogenesis and tumor progression. Nevertheless, this also provides therapeutic opportunities, as cells with defective DDR signaling are directed to rely on compensatory survival pathways, and these vulnerabilities have been exploited for anticancer treatments. Following the impressive success of PARP inhibitors in the treatment of BRCA-mutated breast and ovarian cancers, extensive research has been conducted toward the development of pharmacologic inhibitors of the key components of the DDR signaling pathway. In this review, we discuss the key elements of the DDR pathway and how these molecular components may serve as anticancer treatment targets. We also summarize the recent promising developments in the field of DDR pathway inhibitors, focusing on novel agents beyond PARP inhibitors. Furthermore, we discuss biomarker studies to identify target patients expected to derive maximal clinical benefits as well as combination strategies with other classes of anticancer agents to synergize and optimize the clinical benefits.

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Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models

Cited by 49 publications

References 46 publications

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Genomic Instability and Replicative Stress in Multiple Myeloma: The Final Curtain?

Therapeutic Targeting of DNA Damage Response in Cancer

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