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Preprint WatchModerateJuly 30th, 2026

Endogenous single-cell experiments and stochastic modeling reveal control mechanisms of glucocorticoid receptor dynamics and DUSP1 transcription

Ron, E.; Popinga, A.; Forman, J.; Aguilera, L.; Forero, L.; Munsky, B.

Nuclear glucocorticoid receptor degradation is the dominant mechanism of receptor clearance, the receptor primarily regulates promoter activation rather than later transcriptional steps, and AU-rich element mediated mRNA degradation drives most DUSP1 transcript clearance.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

Claidex holds one NR3C1 failure, exicorilant in metastatic castration-resistant prostate cancer, recorded as an efficacy failure (exicorilant-mcrpc-gr-bypass-fourth-failure). This preprint infers, from single-cell measurements and Chemical Master Equation fitting, that nuclear receptor degradation dominates clearance and that the receptor acts mainly at promoter activation. Both points matter for antagonist programs. A target whose clearance is dominated by nuclear degradation has occupancy kinetics that depend on nuclear residence time rather than on plasma exposure, so a dosing schedule built from plasma pharmacokinetics can miss the window that determines effect. The work is in a cell model under dexamethasone stimulation and does not test an antagonist, so it constrains how target engagement should be measured rather than showing that the target is wrong.

Abstract excerpt

Glucocorticoids activate the glucocorticoid receptor (GR) to suppress inflammation, yet it remains unclear how GR transport dynamics and downstream gene regulation are coordinated within single cells. We combine immunocytochemistry (ICC) and single-molecule fluorescence in situ hybridization (smFISH) to quantify endogenous GR transport and DUSP1 transcription dynamics across thousands of individual cells following dexamethasone (Dex) stimulation. Performing multiple rounds of statistical inference based on Chemical Master Equations (CME), we determine the most likely mechanisms and reaction rates for Dex-driven GR nuclear import; compartment-specific GR degradation; GR-dependent control of the DUSP1 promoter; and DUSP1 transcription, elongation, transport, and degradation. Our inferred model suggests that nuclear GR degradation is the dominant mechanism of receptor clearance, that GR primarily regulates promoter activation, and that time-dependent AU-rich element (ARE)-mediated mRNA degradation contributes heavily to DUSP1 clearance. With these mechanisms, the fully-parameterized model quantitatively predicts joint distributions of GR translocation and decay dynamics, DUSP1 transcription site activity, and nuclear and cytoplasmic DUSP1 mRNA heterogeneity among clonal cells as functions of time and across seven orders of magnitude for Dex induction concentrations. Our results establish an integrated quantitative framework to link receptor dynamics to gene expression heterogeneity and predict single-cell hormone-responsive transcription programs.

Matching Claidex post-mortems

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.