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Small-molecule inhibitors of integrin alpha2beta1 that prevent pathological thrombus formation via an allosteric mechanism.

Publication ,  Journal Article
Miller, MW; Basra, S; Kulp, DW; Billings, PC; Choi, S; Beavers, MP; McCarty, OJT; Zou, Z; Kahn, ML; Bennett, JS; DeGrado, WF
Published in: Proc Natl Acad Sci U S A
January 20, 2009

There is a grave need for safer antiplatelet therapeutics to prevent heart attack and stroke. Agents targeting the interaction of platelets with the diseased vessel wall could impact vascular disease with minimal effects on normal hemostasis. We targeted integrin alpha(2)beta(1), a collagen receptor, because its overexpression is associated with pathological clot formation whereas its absence does not cause severe bleeding. Structure-activity studies led to highly potent and selective small-molecule inhibitors. Responses of integrin alpha(2)beta(1) mutants to these compounds are consistent with a computational model of their mode of inhibition and shed light on the activation mechanism of I-domain-containing integrins. A potent compound was proven efficacious in an animal model of arterial thrombosis, which demonstrates in vivo efficacy for inhibition of this platelet receptor. These results suggest that targeting integrin alpha(2)beta(1) could be a potentially safe, effective approach to long-term therapy for cardiovascular disease.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

January 20, 2009

Volume

106

Issue

3

Start / End Page

719 / 724

Location

United States

Related Subject Headings

  • beta-Alanine
  • Thrombosis
  • Thiazolidines
  • Structure-Activity Relationship
  • Proline
  • Mice, Inbred C57BL
  • Mice
  • Integrin alpha2beta1
  • Humans
  • Fibrinolytic Agents
 

Citation

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Miller, M. W., Basra, S., Kulp, D. W., Billings, P. C., Choi, S., Beavers, M. P., … DeGrado, W. F. (2009). Small-molecule inhibitors of integrin alpha2beta1 that prevent pathological thrombus formation via an allosteric mechanism. Proc Natl Acad Sci U S A, 106(3), 719–724. https://doi.org/10.1073/pnas.0811622106
Miller, Meredith W., Sandeep Basra, Daniel W. Kulp, Paul C. Billings, Sungwook Choi, Mary Pat Beavers, Owen J. T. McCarty, et al. “Small-molecule inhibitors of integrin alpha2beta1 that prevent pathological thrombus formation via an allosteric mechanism.Proc Natl Acad Sci U S A 106, no. 3 (January 20, 2009): 719–24. https://doi.org/10.1073/pnas.0811622106.
Miller MW, Basra S, Kulp DW, Billings PC, Choi S, Beavers MP, et al. Small-molecule inhibitors of integrin alpha2beta1 that prevent pathological thrombus formation via an allosteric mechanism. Proc Natl Acad Sci U S A. 2009 Jan 20;106(3):719–24.
Miller, Meredith W., et al. “Small-molecule inhibitors of integrin alpha2beta1 that prevent pathological thrombus formation via an allosteric mechanism.Proc Natl Acad Sci U S A, vol. 106, no. 3, Jan. 2009, pp. 719–24. Pubmed, doi:10.1073/pnas.0811622106.
Miller MW, Basra S, Kulp DW, Billings PC, Choi S, Beavers MP, McCarty OJT, Zou Z, Kahn ML, Bennett JS, DeGrado WF. Small-molecule inhibitors of integrin alpha2beta1 that prevent pathological thrombus formation via an allosteric mechanism. Proc Natl Acad Sci U S A. 2009 Jan 20;106(3):719–724.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

January 20, 2009

Volume

106

Issue

3

Start / End Page

719 / 724

Location

United States

Related Subject Headings

  • beta-Alanine
  • Thrombosis
  • Thiazolidines
  • Structure-Activity Relationship
  • Proline
  • Mice, Inbred C57BL
  • Mice
  • Integrin alpha2beta1
  • Humans
  • Fibrinolytic Agents