Actin filament dynamics in the cell underlie diverse processes, such as neuronal axon guidance, phagocytosis, platelet activation, organelle movement, cell motility, and cancer metastasis. Understanding actin dynamics at the molecular level will give us insight into these processes and may lead to the identification of new drug targets for the inhibition of tumor cell invasion and metastasis. Small molecules in particular have been instrumental in probing fast process such as cytoskeletal dynamics, although most of these have been discovered by serendipity. This research program centers on the systematic discovery of small molecule tools with which to study actin dynamics in mammalian cells.
Five aims are proposed: 1) To identify the molecular target of G72*, a cyclic peptide that inhibits phosphoinositol(4,5) bisphosphate (PIP2)-induced actin assembly in Xenopus egg extracts. 2) To generate libraries of cell-permeable cyclic and near, end-capped peptides using diversity-oriented synthetic methods. 3) To purify marine sponge extracts and format the resulting semi-pure fractions for high-throughput screening. 4) To screen synthetic and natural product libraries for compounds that inhibit phorbol-12-myristate-13-acetate (PMA)-induced membrane ruffling in mammalian cells. 5) To identify phosphoproteins and proteins that associate specifically with F-actin assembled during membrane ruffling using a combination of affinity chromatography and proteomic profiling methods.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Ault, Grace S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Santa Cruz
Schools of Arts and Sciences
Santa Cruz
United States
Zip Code
Tamble, Craig M; St Onge, Robert P; Giaever, Guri et al. (2011) The synthetic genetic interaction network reveals small molecules that target specific pathways in Sacchromyces cerevisiae. Mol Biosyst 7:2019-30
Combs, David J; Lokey, R Scott (2007) Extended peptoids: a new class of oligomers based on aromatic building blocks. Tetrahedron Lett 48:2679-2682
Gassner, Nadine C; Tamble, Craig M; Bock, Jonathan E et al. (2007) Accelerating the discovery of biologically active small molecules using a high-throughput yeast halo assay. J Nat Prod 70:383-90
Turner, Rushia A; Oliver, Allen G; Lokey, R Scott (2007) Click chemistry as a macrocyclization tool in the solid-phase synthesis of small cyclic peptides. Org Lett 9:5011-4
Schuresko, Laura A; Lokey, R Scott (2007) A practical solid-phase synthesis of Glu7-phalloidin and entry into fluorescent F-actin-binding reagents. Angew Chem Int Ed Engl 46:3547-9
Nehil, Michael T; Tamble, Craig M; Combs, David J et al. (2007) Uncovering genetic relationships using small molecules that selectively target yeast cell cycle mutants. Chem Biol Drug Des 69:258-64
Rezai, Taha; Yu, Bin; Millhauser, Glenn L et al. (2006) Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers. J Am Chem Soc 128:2510-1
Rezai, Taha; Bock, Jonathan E; Zhou, Mai V et al. (2006) Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: successful in silico prediction of the relative permeabilities of cyclic peptides. J Am Chem Soc 128:14073-80
Simon, Rozalyn A; Schuresko, Laura; Dendukuri, Nagamani et al. (2005) One-bead-one-compound library of end-capped dipeptides and deconvolution by microflow NMR. J Comb Chem 7:697-702