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Preprint WatchMildOctober 29th, 2026

Disruption of R2TP-mediated PIKK maturation with de novo designed binders

Gonzalez-Rodriguez, N.; Lopez-Perrote, A.; Reglero, C.; Alegrio-Louro, J.; Failde-Soler, M.; Chacon-Sanchez, C.; Blanco-Romero, E.; Casajus-Pelegay, E.; Lopez-Pernas, G.; Hernandez, I.; Murga, M.; Fernandez-Capetillo, O.; Llorca, O.; Fernandez-Leiro, R.

De novo designed binders disrupt R2TP-mediated maturation of PIKK family kinases including ATR, ATM, DNA-PKcs and mTOR, offering an approach that blocks kinase maturation rather than catalytic activity.

Mild contradiction

1 prior failure

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

Claidex records ceralasertib as a Phase 1 ATR program discontinued on strategic grounds (ceralasertib-atr-advanced-solid-tumours-phase1-programme-discontinuation). This preprint describes a different point of intervention, preventing ATR from maturing rather than inhibiting the mature kinase, which would be expected to carry a distinct selectivity and toxicity profile. It also raises the converse risk, since R2TP serves several PIKKs at once and a maturation blocker is therefore less selective than an active site inhibitor. Anyone reading this as a route around ATR inhibitor tolerability should quantify the simultaneous loss of ATM, DNA-PKcs and mTOR maturation before treating it as a cleaner mechanism.

Abstract excerpt

Phosphatidylinositol 3-kinase-related kinases (PIKKs), including ATM, ATR, DNA-PKcs, SMG1, TRRAP and mTOR, are regulators of gene expression, DNA damage response and metabolism. Their maturation depends on R2TP, a co-chaperone complex comprising the RUVBL1/2 AAA+ ATPase, RPAP3 and PIH1D1. While small-molecule RUVBL1/2 inhibitors have shown promise in cancer models, the presence of RUVBL1/2 in other complexes raises concerns about specificity. Here, we identified the RUVBL1/2-RPAP3 interface as a vulnerability, exploiting it using de novo designed protein binders that occupy the RPAP3-binding site. These subnanomolar-affinity binders dismantle R2TP, depleting levels of all PIKKs while sparing other RUVBL1/2-containing complexes, including chromatin remodelers INO80, SRCAP and TIP60. CryoEM, proteomic, biochemical and cellular analyses revealed that these binders outcompete RPAP3, trapping RUVBL1/2 in a catalytically inactive conformation. Our findings establish selective disruption of R2TP by artificial proteins as a strategy to control PIKK abundance.

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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.