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Preprint WatchModerateJuly 30th, 2026

DIANNeR: label-free RIME resolves lineage-restricted Glucocorticoid Receptor interactomes in normal human tissues

Zhao, W.; Grimes, T. F.; Rose, S. F.; Stenning, J.; Taylor, C.; Baldreki, C.; Goulding, I.; Duke, R.; Baker, S. C.; Montes de Oca, M.; Sinha, A.; Hinley, J.; Fox, J. M.; Kaye, P. M.; Gomm, J. J.; Jones, L. J.; Marangoni, E.; Simoes, B. M.; Clarke, R. B.; Southgate, J.; Bridge, K. S.; Dowle, A.; Holding, A. N.

The glucocorticoid receptor assembles distinct, lineage-restricted protein interactomes across tissues, including a HOXA5-GR interaction present in normal epithelium but undetected in malignant models and an epithelial-restricted SMARCD3-GR interaction with prognostic relevance.

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 reports that the glucocorticoid receptor assembles different protein partners depending on tissue lineage and transformation state, and that some interactions present in normal epithelium disappear in malignant models. That is a direct mechanistic complication for programs that treat the receptor as a single uniform target across indications. If the receptor's functional partners are rewired in tumour tissue, a receptor-level antagonist may engage a complex that no longer carries the signal the program intended to block, which is one candidate explanation for the outcome recorded in exicorilant-mcrpc-gr-bypass-fourth-failure. The finding is descriptive proteomics in normal tissue rather than a therapeutic test, so it raises a design question rather than refuting the target.

Abstract excerpt

Understanding how transcription factors execute tissue-specific programmes requires defining their protein interaction networks in physiologically relevant contexts. However, profiling normal untransformed cells presents fundamental challenges due to intrinsically limited input material. To meet this challenge we integrated data-independent acquisition (DIA), ion mobility separation, and library-free analysis to achieve a 2-fold increase in detection without loss in enrichment. Applied to the glucocorticoid receptor (GR), a ubiquitously expressed nuclear receptor driving pleiotropic responses to standard-of-care anti-inflammatory therapeutics, DIANNeR (DIA-NN enabled RIME) resolves distinct, context-dependent networks across breast, ureter and blood in normal and transformed contexts. Key findings include: detection of a HOXA5-GR interaction in normal epithelium which was undetected in malignant models; an epithelial-restricted SMARCD3-GR interaction with prognostic relevance; and a FOXP3-BCL11B-GR network in primary CD4+ T cell populations undetected by data dependant acquisition (DDA). By defining normal GR tissue interactomes, DIANNeR provides the essential comparator for interpreting network rewiring that drives disease.

Matching Claidex post-mortems

1 of 1 indexed

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.