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January 13, 2009Proceedings of the National Academy of SciencesOpen Access

Small-molecule inhibitors of integrin α 2 β 1 that prevent pathological thrombus formation via an allosteric mechanism

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Key result

Compound 15, a small-molecule inhibitor of integrin α2β1, delayed clot formation by 3-fold (18.7 vs 6.0 minutes, p=0.04) compared to saline in a murine model of arterial thrombosis.

Why the study?

Does an integrin alpha2beta1 small-molecule inhibitor prevent pathological thrombus formation in a murine model of arterial thrombosis?

Population

Wild-type C57BL/6J mice in a ferric chloride-induced carotid artery injury model of arterial thrombosis, and…

Comparison

Integrin alpha2beta1 small-molecule inhibitor 60… vs Normal saline or aspirin 10 mg/kg IV.

Design

Preclinical

Follow-up

30 minutes after injury

Authors

MMMeredith W. MillerSBSandeep BasraDKDaniel W. Kulp

Discussion

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Member takes

Overview

Should not yet alter clinical practice; leaves open integrin α2β1 inhibition as a novel antithrombotic strategy.

Structured PICO

Does an integrin alpha2beta1 small-molecule inhibitor prevent pathological thrombus formation in a murine model of arterial thrombosis?

P
Population
26 wild-type C57BL/6J mice subjected to a ferric chloride-induced carotid artery injury model of arterial thrombosis.
I
Intervention
Integrin alpha2beta1 small-molecule inhibitor (compound 15) 60 mg/kg IV administered 15 minutes before assay.
C
Comparator
Normal saline (negative control) or aspirin 10 mg/kg IV (positive control).
O
Outcome
Time to occlusion (TTO) after ferric chloride-induced carotid artery injury.surrogate

Main Result

Effect estimate: 3-fold delay

Absolute Event Rate: 18.7% vs 6%

p-value: p=0.04

A novel small-molecule inhibitor of integrin alpha2beta1 significantly delayed arterial occlusion in a murine thrombosis model, suggesting a potential new target for antiplatelet therapy.

Limitations

  • Animal model results may not fully translate to human clinical outcomes
  • Inhibitor IC50 values increased under flow conditions compared to static adhesion assays

Cite This Study

Miller et al. (2009) studied Arterial thrombosis (n=26). Compound 15 (integrin α2β1 inhibitor) vs. Normal saline was evaluated on Time to occlusion (TTO) after ferric chloride-induced carotid artery injury (3-fold delay, p=0.04). Compound 15, a small-molecule inhibitor of integrin α2β1, delayed clot formation by 3-fold (18.7 vs 6.0 minutes, p=0.04) compared to saline in a murine model of arterial thrombosis.

synapsesocial.com/papers/6a9546697007bd2ef4e3c77bhttps://doi.org/10.1073/pnas.0811622106
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Also Consider

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  1. 1Structural Basis of Integrin Regulation and Signaling2007 · 1,655 citations
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