Target Identification and Mode of Action Studies

Drug target identification and mode of action studies for molecules discovered through phenotypic screens usually represent a bottleneck in drug discovery. The limited abundance of compound available for characterization studies is an additional fundamental concern in natural products drug discovery, particularly if the structural complexity precludes chemical synthesis in a timely manner. Genomic and proteomic profiling techniques which require only minute amounts of natural products are being applied in our lab to gain insight into how the compounds act globally on the molecular and cellular level. We systematically transfer genome-wide studies used in yeast to infer targets of bioactive compounds into more relevant mammalian systems in order to interrogate more complex pathways. These approaches led to us to identify a novel mode of action for the apratoxin family of anticancer agents.

Target ID and Mode Action

Luesch, H. Mol. BioSyst. 2006, 2, 609–620 (Reproduced by permission of The Royal Society of Chemistry).

We use classical biochemical approaches to study affected molecular pathways and to validate hypotheses derived from global strategies.  We employ affinity chromatography for direct target identification upon labeling of natural products using synthetic organic chemistry.  Cocrystallization of inhibitor–target complexes followed by X-ray crystallography or molecular docking are other techniques applied in our lab to establish binding modes to target proteins.

Sample Publications:

Luesch, H.; Wu, T. Y. H.; Ren, P.; Gray, N. S.; Schultz, P. G.; Supek, F. “A Genome-Wide Overexpression Screen in Yeast for Small-Molecule Target Identification” Chem. Biol. 2005, 12, 55–63.

Luesch, H.; Chanda, S. K.; Raya, R. M.; DeJesus, P. D.; Orth, A. P.; Walker, J. R.; Izpisúa Belmonte, J. C.; Schultz, P. G. “A Functional Genomics Approach to the Mode of Action of Apratoxin A” Nat. Chem. Biol. 2006, 2, 158–167.

Luesch, H. “Towards High-Throughput Characterization of Small Molecule Mechanisms of Action” Mol. BioSyst. 2006, 2, 609–620.

Liu, Y.; Law, B. K.; Luesch, H. “Apratoxin A Reversibly Inhibits the Secretory Pathway by Preventing Cotranslational Translocation” Mol. Pharmacol. 2009, 76, 91–104.

Taori, K.; Liu, Y.; Paul, V. J.; Luesch, H. “Combinatorial Strategies by Marine Cyanobacteria: Symplostatin 4, an Antimitotic Natural Dolastatin 10/15 Hybrid that Synergizes with the Coproduced HDAC Inhibitor Largazole” ChemBioChem 2009, 10, 1634–1639.

Liu, Y.; Salvador, L. A.; Byeon, S.; Ying, Y.; Kwan, J. C.; Law, B. K.; Hong, J.; Luesch, H. “Anticolon Cancer Activity of Largazole, a Marine-Derived Tunable Histone Deacetylase Inhibitor” J. Pharmacol. Exp. Ther. 2010, 335, 351–361.

Salvador, L. A.; Taori, K.; Biggs, J. S.; Jakoncic, J.; Ostrov, D. A.; Paul, V. J.; Luesch, H. “Potent Elastase Inhibitors from Cyanobacteria: Structural Basis and Mechanisms Mediating Cytoprotective and Anti-Inflammatory Effects in Bronchial Epithelial Cells” J. Med. Chem. 2013, 56, 1276‒1290.


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