ArticleOncotarget2015
Identification of novel, in vivo active Chk1 inhibitors utilizing structure guided drug design.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 44 citations in OpenAlex.
- The Potential for Targeting GCancers · 2024Review
- Chk1 inhibitor-induced DNA damage increases BFL1 and decreases BIM but does not protect human cancer cell lines from Chk1 inhibitor-induced apoptosis.American journal of cancer research · 2022Article
- Targeting DYRK1A/B kinases to modulate p21-cyclin D1-p27 signalling and induce anti-tumour activity in a model of human glioblastoma.Journal of cellular and molecular medicine · 2021Article
- Checkpoint Kinase 1 (Chk1) inhibition fails to activate the Stimulator of Interferon Genes (STING) innate immune signalling in a human coculture cancer system.Molecular biomedicine · 2021Article
- Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer.International journal of molecular sciences · 2020Article
- Participation of the ATR/CHK1 pathway in replicative stress targeted therapy of high-grade ovarian cancer.Journal of hematology & oncology · 2020Review
- Effects of a checkpoint kinase inhibitor, AZD7762, on tumor suppression and bone remodeling.International journal of oncology · 2018Article
- Article
- ATR/CHK1 inhibitors and cancer therapy.Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology · 2018Review
- Inhibiting checkpoint kinase 1 protects bone from bone resorption by mammary tumor in a mouse model.Oncotarget · 2018Article
- A high content, high throughput cellular thermal stability assay for measuring drug-target engagement in living cells.PloS one · 2018Article
- Targeting the ATR-CHK1 Axis in Cancer Therapy.Cancers · 2017Review
- Alternative Chk1-independent S/M checkpoint in somatic cells that prevents premature mitotic entry.Medical oncology (Northwood, London, England) · 2017Article
- Review
- Modification of tumour cell metabolism modulates sensitivity to Chk1 inhibitor-induced DNA damage.Scientific reports · 2017Article
- The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models.PloS one · 2017Article
- Inhibition of Chk1 with the small molecule inhibitor V158411 induces DNA damage and cell death in an unperturbed S-phase.Oncotarget · 2016Article
- Tumour growth environment modulates Chk1 signalling pathways and Chk1 inhibitor sensitivity.Scientific reports · 2016Article
- LY2603618, a selective CHK1 inhibitor, enhances the anti-tumor effect of gemcitabine in xenograft tumor models.Investigational new drugs · 2016Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
Chk1 kinase is a critical component of the DNA damage response checkpoint especially in cancer cells and targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumor activity of DNA damaging chemotherapy drugs. Fragment elaboration by structure guided design was utilized to identify and develop a novel series of Chk1 inhibitors culminating in the identification of V158411, a potent ATP-competitive inhibitor of the Chk1 and Chk2 kinases. V158411 abrogated gemcitabine and camptothecin induced cell cycle checkpoints, resulting in the expected modulation of cell cycle proteins and increased cell death in cancer cells. V158411 potentiated the cytotoxicity of gemcitabine, cisplatin, SN38 and camptothecin in a variety of p53 deficient human tumor cell lines in vitro, p53 proficient cells were unaffected. In nude mice, V158411 showed minimal toxicity as a single agent and in combination with irinotecan. In tumor bearing animals, V158411 was detected at high levels in the tumor with a long elimination half-life; no pharmacologically significant in vivo drug-drug interactions with irinotecan were identified through analysis of the pharmacokinetic profiles. V158411 potentiated the anti-tumor activity of irinotecan in a variety of human colon tumor xenograft models without additional systemic toxicity. These results demonstrate the opportunity for combining V158411 with standard of care chemotherapeutic agents to potentiate the therapeutic efficacy of these agents without increasing their toxicity to normal cells. Thus, V158411 would warrant further clinical evaluation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.