Craig M' Crews, Ph'D'

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Small Molecule Screening in Academia
Craig M. Crews, Ph.D. Associate Professor
Molecular, Cellular, and Developmental
Biology Pharmacology Chemistry
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Small Molecules as Cellular Probes
temporal resolution
spatial resolution
reversibility
specificity
transferable
Genetic manipulations
RNAi
Inhibitory Ab
Small molecule
Mayer, Trends Cell Biol., 2003
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Natural Product Probes of Cell Biology
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Natural Product Probes of Cell Biology
Taxol
Cytochalasin B
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Natural Product Probes of Cell Biology
Taxol
FK506
Cytochalasin B
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Natural Product Probes of Cell Biology
Taxol
?-amanitin
FK506
Cycloheximide
Cytochalasin B
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Natural Product Probes of Cell Biology
Taxol
?-amanitin
FK506
Cycloheximide
Cytochalasin B
Phorbol Ester
Okadaic Acid
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Small Molecule Screening in Academia
Natural Products can be very useful but most
result from pharmaceutical bioassays.
Why should academic researchers limit ourselves
to pharmaceutical targets?
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Requirements for HTS Screening
I. Liquid transfer robotics
II. Readout instrumentation, e.g. Plate
reader, automated microscope
III. Small molecule libraries
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Small Molecule Library Suppliers
Asinex (Russia) Comgenex (Hungary) Enamine
(Ukraine) Maybridge (Russia) Zelinsky Institute
(Russia)
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Academic Small Molecule Screening Approaches
Mayer, Trends Cell Biol., 2003
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Monastrol
Science. 1999 Oct 29286(5441)971-4.
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Monastrol
The target of monastrol is the mitotic motor
protein Eg5, a bipolar kinesin known to be
required for spindle bipolarity.
Science. 1999 Oct 29286(5441)971-4.
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Myosin II Inhibitor Screen
Nature Cell Biology 4, 83 - 88 (2001)
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Blebbistatin Inhibits Non-muscle Myosin II
Nature Structural Molecular Biology 12, 378 -
379 (2005)
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Blebbistatin
Reversible inhibition of M2 cell blebbing by 100
µM()-blebbistatin.
Science 2003 299 pp. 1743 - 1747
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Blebbistatin
100µM Blebbistatin
Control anaphase and cytokinesis in XTC cells
Science 2003 299 pp. 1743 - 1747
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Chemical Genetic Suppressor Screens
Fli-GFP
Dev Biol. 2002 248(2)307-18
Gridlock
Nat Biotechnol. 2004 22(5)595-9
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Future Directions

• NIH ChemBank

• AcademicIndustrial Collaborations

• Novartis Institutes for Biomedical Research
  (NIBR)