This tool is for research exploration only. It is not a medical device and does not provide medical advice. Drug candidates, evidence scores, and AI-generated content are not clinical recommendations. Always consult your medical team before making any treatment decisions.
Ceralasertib
AZD6738
ATR kinase inhibitor
Evidence Score
33
Selective, orally bioavailable inhibitor of ATR (ataxia telangiectasia and Rad3-related) serine/threonine kinase. The mechanistic rationale is synthetic lethality with ATRX loss: in SDHB-driven metastatic pheochromocytoma and paraganglioma, ATRX co-mutations occur in ~30–40% of cases (confirmed by multi-omics analysis, PMID 42230482) and are the strongest genomic predictor of malignancy in this subtype. ATRX loss triggers the Alternative Lengthening of Telomeres (ALT) pathway, creating constitutive telomeric replication stress — G-quadruplex accumulation, R-loops, fragile telomeres — that generates an absolute dependency on ATR kinase for stalled-fork resolution and survival. Flynn et al. (Science 2015, PMID 25614623) established that ATRX-loss/ALT-positive cells are 10–30× more sensitive to ATR inhibition than ALT-negative controls across multiple cancer types, a synthetic lethality that is absent from ATRX-wild-type cells. Ceralasertib is in Phase 1/2 clinical development; the OLAPCO Phase 2 trial (NCT03787680) tests ceralasertib + olaparib in DNA-damage-response-deficient tumors including ATRX-loss contexts. Key limitation: no dedicated PPGL or SDH-deficient-specific trial data exists; the ~30–40% ATRX co-mutation prevalence means this strategy applies only to the ATRX-loss subgroup, requiring prospective ATRX genotyping to identify eligible patients.
In SDHB-driven metastatic pheochromocytoma and paraganglioma, ATRX co-mutations occur in ~30–40% of cases and are among the strongest genomic predictors of malignancy (confirmed by multi-omics profiling: PMID 42230482). ATRX loss activates the Alternative Lengthening of Telomeres (ALT) pathway — a recombination-based telomere maintenance mechanism — which creates constitutive replication stress at telomeric sequences through G-quadruplex DNA accumulation, R-loop formation, and fragile telomeres. ALT-positive cells are rendered hypersensitive to ATR kinase inhibition: Flynn et al. (Science 2015, PMID 25614623) demonstrated that ATRX-loss/ALT-positive cancer cells are 10–30× more sensitive to ATR inhibitors than ALT-negative cells across multiple cancer types, establishing a synthetic lethality that is absent in ATRX-wild-type tumors.
Upstream event:
SDH loss (particularly SDHB mutation) → epigenetic instability → ATRX co-mutation → ALT pathway activation → constitutive telomeric replication stress → ATR dependency
Downstream effects:
ATR
Ataxia telangiectasia and Rad3-related protein kinase
The primary replication stress checkpoint kinase. Phosphorylates and activates CHK1, stabilizes stalled replication forks, and coordinates origin firing suppression under genotoxic stress. In ATRX-loss/ALT cells, constitutive telomeric G-quadruplex formation and R-loop accumulation generate persistent stalled replication forks that require ATR signaling for resolution; ALT cells are therefore dependent on ATR for survival. Flynn et al. (Science 2015, PMID 25614623) established that ATR inhibition is synthetically lethal with ALT in multiple cancer types with ATRX or DAXX loss, showing 10–30× greater sensitivity in ALT-positive versus ALT-negative cells.
UniProt: Q13535
Evidence from PubMed, OpenTargets, and ChEMBL will appear here once external data integration is enabled.
Coming in Phase 3
For research exploration only — not medical advice. Consult your doctor before acting on any information.
Have Claude analyze this drug's repurposing potential for SDH-deficient diseases.