Inhibitors of Platelet Integrin alphallb-beta3: Summary
The alphaIIbbeta3 receptor plays a vital role in hemostasis and thrombosis, where receptor deficiency causes the hemorrhagic disorder, Glanzmann thrombasthenia, and uncontrolled receptor activation causes thrombosis and blood vessel occlusion. Small molecule inhibitors of alphaIIbbeta3, tirofiban and eptifibatide, have undesirable side effects thought to arise from conformational changes in more ..
NIH Molecular Libraries Probe Production Network [MLPCN]
NIH Chemical Genomics Center [NCGC]
MLPCN Grant: 1 R03 MH083257-01
Assay Provider: Barry Coller, Rockefeller University
NCGC Assay Overview:
The alphaIIbbeta3 receptor plays a vital role in hemostasis and thrombosis, where receptor deficiency causes the hemorrhagic disorder, Glanzmann thrombasthenia, and uncontrolled receptor activation causes thrombosis and blood vessel occlusion. Small molecule inhibitors of alphaIIbbeta3, tirofiban and eptifibatide, have undesirable side effects thought to arise from conformational changes in alphaIIbbeta3. These changes transiently activate the receptor to cause spontaneous platelet aggregation and thrombus formation. The goal of this project is to identify new alphaIIbbeta3 antagonists that do not activate the receptor or initiate conformational changes that expose novel epitopes.
RUC-1, a compound containing a thiadiazolopyrimidinone core, inhibits alphaIIbbeta3 with ~10 uM IC50 in vitro (Blue et al., 2008) and shows anti-thrombotic effects in vivo (Blue et al., 2009). Analogs of RUC-1 were synthesized and tested in platelet binding (AID 2634) and platelet aggregation (AID 2639) assays to assess their activity. Selectivity was determined by a cell-based alphaVbeta3 binding assay (AID 2628). This work identified RUC-1 analogs that were selective and more potent inhibitors of alphaIIbbeta3. A probe compound (CID 44820665; probe number ML165) was identified later.
Blue R, Murcia M, Karan C, Jirouskova M, and Coller BS. Application of high-throughput screening to identify a novel alphaIIb-specific small- molecule inhibitor of alphaIIbbeta3-mediated platelet interaction with fibrinogen. Blood. 2008, 111:1248-56
Blue R, Kowalska MA, Hirsch J, Murcia M, Janczak CA, Harrington A, Jirouskova M, Li J, Fuentes R, Thornton MA, Filizola M, Poncz M, and Coller BS. Structural and therapeutic insights from the species specificity and in vivo antithrombotic activity of a novel alphaIIb-specific alphaIIbbeta3 antagonist. Blood. 2009, 114:195-201
NCGC Assay Protocol Summary:
Please refer to AIDs 2634, 2639, 2628 for detailed assay protocols.
This summary is written for the purposes of summarizing the probe activities from the project. MLSCN probes are given a score of 100. Molecules in the prior art are given a score of 80. Other, less active molecules in the same chemical series as the probe molecules are given a score of 50. Inconclusive compounds are given a score of 20. Inactive analogues from these series are given a score of 0.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML165
PubChem Substance ID (SID) for probe 1: 89449681
PubChem Compound ID (CID) for probe 1: 44820665
Probe type for probe 1: Inhibitor
IC50/EC50 (nM) for probe 1: 1100
Target for probe 1: AlphallbBeta3 receptor (gi: 121945354)
Disease relevance for probe 1: Glanzmann thrombasthenia Rare Disease
Anti-target for probe 1: alphaVbeta3 receptor
Fold selectivity for probe 1: >100
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK56230/ (ID: 2509288)
Grant number for probe 1: MH083257-01
NCBI Book chapter title for probe 1: Inhibitors of Platelet Integrin allb▀3
Data Table (Concise)