ArticleACS chemical biology2013
CH-01 is a hypoxia-activated prodrug that sensitizes cells to hypoxia/reoxygenation through inhibition of Chk1 and Aurora A.
Article in ACS chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 65 citations in OpenAlex.
- Article
- Indolequinone-Based Hypoxia-Activated Proteolysis Targeting Chimeras Selectively Degrade BRD4 in Hypoxic Cancer Cells.Journal of the American Chemical Society · 2025Article
- A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy.Nature communications · 2024Article
- Article
- Two Color Imaging of Different Hypoxia Levels in Cancer Cells.Journal of the American Chemical Society · 2023Article
- Targeting DNA topoisomerase IIα (TOP2A) in the hypoxic tumour microenvironment using unidirectional hypoxia-activated prodrugs (uHAPs).IUBMB life · 2023Review
- Hypoxia signaling: Challenges and opportunities for cancer therapy.Seminars in cancer biology · 2022Review
- Therapeutic targeting of the hypoxic tumour microenvironment.Nature reviews. Clinical oncology · 2021Review
- Development and pre-clinical testing of a novel hypoxia-activated KDAC inhibitor.Cell chemical biology · 2021Article
- Design, synthesis and biological evaluations of a long-acting, hypoxia-activated prodrug of fasudil, a ROCK inhibitor, to reduce its systemic side-effects.Journal of controlled release : official journal of the Controlled Release Society · 2021Article
- Article
- Hypoxia-targeted drug delivery.Chemical Society reviews · 2019Review
- ATR/CHK1 inhibitors and cancer therapy.Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology · 2018Review
- Hypoxia-activated prodrugs and redox-responsive nanocarriers.International journal of nanomedicine · 2018Review
- Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Review
- Bioreductively activatable prodrug conjugates of phenstatin designed to target tumor hypoxia.Bioorganic & medicinal chemistry letters · 2017Article
- CYP450 Enzymes Effect Oxygen-Dependent Reduction of Azide-Based Fluorogenic Dyes.ACS central science · 2017Article
- Design, synthesis and evaluation of molecularly targeted hypoxia-activated prodrugs.Nature protocols · 2016Article
- Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs.Cancer chemotherapy and pharmacology · 2016Review
- Enhancement of hypoxia-activated prodrug TH-302 anti-tumor activity by Chk1 inhibition.BMC cancer · 2015Article
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
The increased resistance of hypoxic cells to all forms of cancer therapy presents a major barrier to the successful treatment of most solid tumors. Inhibition of the essential kinase Checkpoint kinase 1 (Chk1) has been described as a promising cancer therapy for tumors with high levels of hypoxia-induced replication stress. However, as inhibition of Chk1 affects normal replication and induces DNA damage, these agents also have the potential to induce genomic instability and contribute to tumorigenesis. To overcome this problem, we have developed a bioreductive prodrug, which functions as a Chk1/Aurora A inhibitor specifically in hypoxic conditions. To achieve this activity, a key functionality on the Chk1 inhibitor (CH-01) is masked by a bioreductive group, rendering the compound inactive as a Chk1/Aurora A inhibitor. Reduction of the bioreductive group nitro moiety, under hypoxic conditions, reveals an electron-donating substituent that leads to fragmentation of the molecule, affording the active inhibitor. Most importantly, we show a significant loss of viability in cancer cell lines exposed to hypoxia in the presence of CH-01. This novel approach targets the most aggressive and therapy-resistant tumor fraction while protecting normal tissue from therapy-induced genomic instability.
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