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September 19, 2026Open Access

BTK degrader NX-5948 markedly reduces arterial thrombosis in mice without increasing bleeding time.

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Why the study?

Current antithrombotic therapies reduce thrombotic events but are limited by bleeding risk; selective BTK degradation may provide antithrombotic benefits without affecting hemostasis.

Does selective degradation of platelet BTK by PROTAC NX-5948 reduce thrombosis without affecting hemostasis in preclinical models?

Population

In vitro human platelets and in vivo mouse model

Comparison

BTK degraders NX-2127 and NX-5948 vs control

Design

Preclinical experimental study

Key result

The BTK degrader NX-5948 selectively degraded platelet BTK and markedly reduced in vivo arterial thrombosis in mice without increasing bleeding time.

Authors

CMCarl J. MayJTJustin S. TroryCWConnor E. Webb

Discussion

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Overview

Hypothesis-generating for antithrombotic therapy sparing hemostasis; human trials needed before any clinical consideration.

Key Points

  • To determine whether targeted degradation of platelet Bruton tyrosine kinase (BTK) using PROTAC degraders can achieve antithrombotic efficacy without disrupting normal hemostatic function.
  • Tested BTK degraders NX-2127 and NX-5948 in washed human platelets, platelet-rich plasma, and whole blood, utilizing proteomic analyses to evaluate off-target effects.
  • Assessed in vitro and ex vivo platelet activation, integrin αIIbβ3 activation, and aggregation stimulated by collagen-related peptide versus thrombin receptor pathways.
  • Administered NX-5948 to mice to quantify in vivo arterial thrombosis inhibition and tail bleeding times.
  • NX-5948 demonstrated potent, concentration-dependent degradation of platelet BTK with superior kinetics and no hook effect or major off-target proteomic changes.
  • BTK degradation selectively impaired collagen-related peptide-mediated integrin αIIbβ3 activation, P-selectin expression, and aggregation, while protease-activated receptor 1 signaling remained intact.
  • Dosing in mice led to marked reductions in arterial thrombosis in vivo without prolonging bleeding time.

Structured PICO

Does selective degradation of platelet BTK by PROTAC NX-5948 reduce thrombosis without affecting hemostasis in preclinical models?

P
Population
In vitro platelets (washed platelets, platelet-rich plasma, whole blood) and in vivo mouse model
I
Intervention
BTK degraders NX-2127 and NX-5948
O
Outcome
BTK degradation, platelet function (integrin αIIbβ3 activation, P-selectin expression, platelet aggregation), in vitro thrombosis, in vivo arterial thrombosis, and bleeding timesurrogate

Selective degradation of platelet BTK by NX-5948 offers a promising antithrombotic strategy that decouples thrombosis prevention from bleeding risk.

Cite This Study

May et al. (2026) studied Thrombosis. NX-5948 was evaluated on Arterial thrombosis and bleeding time. The BTK degrader NX-5948 selectively degraded platelet BTK and markedly reduced in vivo arterial thrombosis in mice without increasing bleeding time.

synapsesocial.com/papers/6aae47640c69660b71ecc641https://doi.org/10.1182/bloodadvances.2026019769
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Selective degradation of platelet BTK by PROTAC NX-5948 provides antithrombotic benefits without affecting haemostasis2026
  2. 2Inhibition of platelet kinase signaling and scaffolding activities with small molecule proteolysis-targeting chimeras (PROTACs)2025
  3. 3Efficacy and mechanism of BTK degrader nx-5948 in secondary hemophagocytic lymphohistiocytosis2025
  4. 4Comparison of variably specific Bruton tyrosine kinase inhibitors on platelet aggregation mediated by Fcγ receptor (FcγR) IIa, glycoprotein VI, and platelet endothelial aggregation receptor (PEAR) 1: implications for Bruton tyrosine kinase inhibitors as antithrombotic therapy2026
  5. 5Involvement of Btk in Cardiovascular Disease and Its Therapeutic Targeting2026 · 2 citations