ArticleProceedings of the National Academy of Sciences of the United States of America2022
CRY2 isoform selectivity of a circadian clock modulator with antiglioblastoma efficacy.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 38 citations in OpenAlex.
- Circadian rhythms in health and disease.Molecular biomedicine · 2026Review
- Time matters: circadian genetics and the molecular logic of human health and disease.Nature reviews. Genetics · 2026Review
- Chemical biology approaches to study and target circadian clocks and their components.FEBS letters · 2026Review
- Biochemical mechanism of the mammalian circadian clock.FEBS letters · 2026Review
- Temporal dynamics in cancer immunotherapy: the interplay between circadian rhythms, tumor microenvironment, and immune checkpoint blockade.Journal of the National Cancer Center · 2026Review
- Glioblastoma stem cells resist cuproptosis with circadian variation of copper levels.The Journal of clinical investigation · 2026Article
- Circadian clock and cancer.Military Medical Research · 2026Review
- Structure of European robin cryptochrome 1 reveals a role in circadian rhythms, not magnetoreception.iScience · 2025Article
- Personalized chronotherapy in glioblastoma: integrating circadian profiling and PK-PD modelling to optimize temozolomide timing.NPJ precision oncology · 2025Article
- Targeting Cryptochromes in Chronic Diseases.Cell biology international · 2025Review
- Advancing clinical response against glioblastoma: Evaluating SHP1705 CRY2 activator efficacy in preclinical models and safety in phase I trials.Neuro-oncology · 2025Article
- Spatiotemporal Control Over Circadian Rhythms With Light.Medicinal research reviews · 2025Review
- Integrated machine learning constructed a circadian-rhythm-related model to assess clinical outcomes and therapeutic advantages in hepatocellular carcinoma.Translational cancer research · 2025Article
- Development of compounds for targeted degradation of mammalian cryptochrome proteins.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2025Article
- Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis.Nature cancer · 2024Review
- Learning from circadian rhythm to transform cancer prevention, prognosis, and survivorship care.Trends in cancer · 2024Review
- Molecular mechanisms of tumour development in glioblastoma: an emerging role for the circadian clock.NPJ precision oncology · 2024Review
- Timely Questions Emerging in Chronobiology: The Circadian Clock Keeps on Ticking.Journal of circadian rhythms · 2024Review
- Metabolic and chemical architecture of the mammalian circadian clock.Cell chemical biology · 2023Review
- Computational modeling and synthesis of pyridine variants of benzoyl-phenoxy-acetamide with high glioblastoma cytotoxicity and brain tumor penetration.Scientific reports · 2023Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
The mammalian cryptochrome isoforms, CRY1 and CRY2, are core circadian clock regulators that work redundantly. Recent studies revealed distinct roles of these closely related homologs in clock output pathways. Isoform-selective control of CRY1 and CRY2 is critical for further understanding their redundant and distinct roles. KL001 was the first identified small-molecule CRY modulator that activates both CRY1 and CRY2. SHP656 is an orally available KL001 derivative and has shown efficacy in blood glucose control and inhibition of glioblastoma stem cell (GSC) growth in animal models. However, CRY isoform selectivity of SHP656 was uncharacterized, limiting understanding of the roles of CRY1 and CRY2. Here, we report the elucidation of CRY2 selectivity of SHP656. SHP656 lengthened cellular circadian period in a CRY2-dependent manner and selectively interacted with CRY2. By determining the X-ray crystal structure of CRY2 in complex with SHP656 and performing molecular dynamics simulations, we elucidated compound interaction mechanisms. SHP656 binding was compatible with the intrinsic CRY2 gatekeeper W417 "in" orientation and also a close "further in" conformation. Perturbation of W417 interaction with the lid loop resulted in a reduced effect of SHP656 on CRY2, supporting an important role of gatekeeper orientation in isoform selectivity. We also identified the R form of SHP656 (called SHP1703) as the active isomer. Treatment with SHP1703 effectively reduced GSC viability. Our results suggest a direct role of CRY2 in glioblastoma antitumorigenesis and provide a rationale for the selective modulation of CRY isoforms in the therapeutic treatment of glioblastoma and other circadian clock-related diseases.
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