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Preprint WatchMildOctober 28th, 2026

Graded and cross-reactive JAK-receptor interactions broaden the one-receptor, one-JAK rule

Venkat Ramani, M. K.; Ross, P. L.; Guo, K.; Leuz, Y.; Bonilla, J.; Hardtke, H. A.; Mendoza, J. L.

JAK-receptor pairing is graded and cross-reactive rather than exclusive and constitutive, with TYK2 binding IL2R-beta far more tightly than JAK1 and GM-CSF receptor binding both kinases.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

The preprint reports that JAK-receptor pairing is graded and cross-reactive rather than exclusive and constitutive, with dissociation constants spanning tens of nanomolar to tens of micromolar across 32 receptor intracellular domains, IL2R-beta binding TYK2 far more tightly than JAK1, and GM-CSF signalling proceeding through JAK1 when TYK2 and other JAKs were inhibited. Claidex holds one TYK2 failure, deucravacitinib-tyk2-hidradenitis-suppurativa-phase2-funding-withdrawal, which ended through funding withdrawal rather than on efficacy or safety grounds. The preprint bears on how TYK2 selectivity should be read, because if a receptor can signal through an alternative JAK when TYK2 is blocked, then selectivity at the protein level does not guarantee pathway selectivity in cells. Flagged MILD because the one matching failure was not an efficacy failure.

Abstract excerpt

Cytokine receptors signal through a dedicated Janus kinase (JAK) that is thought to be constitutively bound to the receptor intracellular domain (ICD). We tested this one-receptor, one-JAK model biophysically. A bead-based screen of JAK1 and TYK2 against 32 receptor ICDs, confirmed by microscale thermophoresis to measure affinity, revealed dissociation constants spanning tens of nanomolar to tens of micromolar, indicating that many interactions are not high-affinity and may not be constitutive. Binding was also widely cross-reactive: GMCSFR bound both JAK1 and TYK2, and IL2R{beta} bound TYK2 far more tightly than JAK1. In cells, GM-CSF signaled through JAK1 when JAK2, JAK3, and TYK2 were inhibited. JAK-receptor pairing is therefore permissive and graded rather than exclusive and constitutive.

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.