Paul J. Hergenrother

Associate Professor of Chemistry

Professor Hergenrother received his B.S. in chemistry from the University of Notre Dame in 1994. He went on to the University of Texas at Austin and obtained his Ph.D. in 1999; during this time Paul was the recipient of an American Chemical Society graduate student fellowship and the Roche Award for Excellence in Organic Chemistry. After an American Cancer Society post-doctoral fellowship at Harvard University, he joined the faculty at Illinois in 2001. His research interests are in the areas of synthetic organic chemistry, chemical biology, and biochemistry.

Research

The overarching goal of our research is to use small organic compounds to identify novel cellular targets that can be exploited in the treatment of diseases including cancer, neurodegeneration, and drug-resistant bacteria. The compounds used to validate these novel drug targets are identified through a variety of approaches, including natural product synthesis, combinatorial chemistry, structure-based design, and high-throughput screening. In the process, novel methods for the synthesis of various chemical building blocks and for biological assays often need to be developed. In addition, we work closely with the local medical community and perform tests directly on patient samples.

Novel anti-cancer targets.

There are currently no treatments for certain cancers such as colon cancer and late-stage malignant melanoma. We have synthesized a series of compounds, the triphenylmethylamides (TPMAs), which powerfully induce programmed cell death in melanoma and are comparatively less toxic to non-cancerous cells. The TPMAs appear to function via a novel biochemical mechanism, and cause arrest of cancer cells in the G1 phase of the cell cycle. In a separate series of experiments, through high-throughput screening and combinatorial synthesis we have identified compounds that directly induce programmed cell death in a variety of cancer cells; these compounds are currently being tested against patient samples and in mouse models.

Novel targets for drug-resistant bacteria.

Every year 90,000 people in the U.S. alone die from bacterial infections they acquire at hospitals. Many of these bacteria become resistant to antibiotics by taking up a plasmid, a small piece of circular DNA that encodes for the proteins that mediate antibiotic resistance. We have recently identified anti-plasmid agents—compounds that inhibit plasmid replication and thus sensitize bacteria to traditional antibiotics. We have focused sharply on Vancomycin-Resistant Enterococci (VRE); we have obtained clinical VRE isolates from local medical centers and are defining plasmid-encoded resistance in VRE. This work has spawned a large and general effort in the laboratory to develop a paradigm for small molecule-RNA binding. We have identified small molecule modules that bind tightly and specifically to defined regions of RNA secondary structure, including RNA hairpin loops and bulges. We are connecting such modules to target individual mRNAs in the cell with exquisite affinity and selectivity.

Publications

Thomas, J. R.; Hergenrother, P. J. "Targeting RNA with Small Molecules" Chem. Rev. 2008, in press

Wang, N. R.; Hergenrother, P. J. "A Continuous Fluorometric Assay for the Assessment of MazF Ribonuclease Activity" Anal. Biochem. 2007, 371, 173-183.

Nottbohm, A. C.; Dothager, R. S.; Putt, K. S.; Hoyt, M. T.; Hergenrother, P. J. "A Novel Colorimetric Substrate for Poly (ADP-Ribose) Polymerase-1, VPARP, and Tankyrase-1" Angew. Chem. Int. Ed. 2007, 46, 2066-2069.

Sienkiewicz, P.; Ciolino, H.; Leslie, B. J.; Hergenrother, P. J.; Singletary, K.; Yeh, G. C. "A Novel Synthetic Analogue of a Constituent of Isodon excisus Inhibits Transcription of CYP1A1, -1A2, and -1B1 by Preventing Activation of the Aryl Hydrocarbon Receptor" Carcinogenesis, 2007, 28, 1052-1057.

Moritz, E. M.; Hergenrother, P. J. "Toxin-Antitoxin System are Ubiquitous and Plasmid-Encoded in Vancomycin-Resistant Enterococci" Proc. Natl. Acad. Sci. 2007, 104, 311-316.

Putt, K. S.; Nesterenko, V.; Dothager, R. S.; Hergenrother, P. J. "The Compound 13-D Selectively Induces Apoptosis in White Blood Cancers Versus Other Cancer Cell Types" ChemBioChem 2006, 7, 1916-1922.

Putt, K. S.; Chen, G. W.; Pearson, J. M.; Sandhorst, J. S.; Hoagland, M. S.; Kwon, J.-T.; Hwang, S.-K.; Jin, H.; Churchwell, M. I.; Cho, M.-H.; Doerge, D. R.; Helferich, W. G.; Hergenrother, P. J. "Small Molecule Activation of Procaspase-3 to Caspase-3 as a Personalized Anti-Cancer Strategy" Nature Chem. Biol. 2006, 2, 543-550. (Highlighted in Nature Chem. Biol. 2006, 2, 509-510; Chem. Eng. News 2006, 11; Nature Rev. Drug Discovery 2006, 5.)

Thomas, J. R.; Liu, X.; Hergenrother, P. J. "Biochemical and Thermodynamic Characterization of Compounds that Bind to RNA Hairpin Loops: Towards an Understanding of Selectivity" Biochemistry 2006, 45, 10928-10938.

Musk, D. J.; Hergenrother, P. J. "Chemical Countermeasures for the Control of Bacterial Biofilms: Effective Compounds and Promising Targets" Curr. Med. Chem. 2006, 13, 2163-2177 (review).

Thomas, J. R.; Liu, X.; Hergenrother, P. J. "Size-Specific Ligands for RNA Hairpin Loops" J. Am. Chem. Soc. 2005, 127, 12434-12435.

Musk, D. J.; Banko, D. A.; Hergenrother, P. J. "Iron Salts Perturb Biofilm Formation and Disrupt Existing Biofilms of Pseudomonas aeruginosa."Chem. Biol. 2005, 12, 789-796. Highlighted in Chem. Biol. 2005, 12, 721-723. (Highlighted in Chem. Biol. 2005, 12, 721-723.)

Dothager, R. S.; Putt, K. S.; Allen, B. J.; Leslie, B. J.; Nesterenko, V.; Hergenrother, P. J. "Synthesis and Identification of Small Molecules that Potently Induce Apoptosis in Melanoma Cells Through G1 Cell Cycle Arrest"J. Am. Chem. Soc 2005 127, 8686-8696. (Highlighted in Chem. Eng. News 2005, 83, 17.)

DeNap, J. C. B.; Thomas, J. R.; Musk, D. J.; Hergenrother, P. J. "Combating Drug-Resistant Bacteria: Small Molecule Mimics of Plasmid Incompatibility as Antiplasmid Compounds" J Am. Chem. Soc. 2004, 126, 15402-15404. (Highlighted in Chem. Eng. News 2004 82, 46, 6; Chem. Eng. News 2004 82, 51, 56-57; Drug Discovery Today 2005, 10, 163; National Geographic, April 2005. Science News 2005, 167, 347-348. Earth & Sky, August 3, 2005 broadcast.)

Awards

Highlights

Doctors in the UIUC School of Veterinary Medicine are enrolling dogs with cancer for a Phase I Clinical Trial with one of the anti-cancer compounds discovered in the Hergenrother laboratory.

On July 23, 2007 BioLineRx announced the licensing of an anti-cancer agent developed in the Hergenrother laboratories

Putt, K. S.; Chen, G. W.; Pearson, J. M.; Sandhorst, J. S.; Hoagland, M. S.; Kwon, J.-T.; Hwang, S.-K.; Jin, H.; Churchwell, M. I.; Cho, M.-H.; Doerge, D. R.; Helferich, W. G.; Hergenrother, P. J. "Small-Molecule Activation of Procaspase-3 to Caspase-3 as a Personalized Anticancer Strategy" Nature Chemical Biology 2006, 2, 543-50.

Musk, D.J.; Banko, D.A.; Hergenrother, P.J. "Iron Salts Perturb Biofilm Formation and Disrupt Existing Biofilms of Pseudomonas aeruginosa." Chem. Biol., 2005, 12, 789-796.
Chemistry & Biology Highlight

Dothager, R.S.; Putt, K.S.; Allen, B.J.; Leslie, B.J.; Nesterenko, V.; Hergenrother, P.J. "Synthesis and Identification of Small Molecules that Potently Induce Apoptosis in Melanoma Cell Through G1 Cell Cycle Arrest." J. Am. Chem. Soc., 2005, 127, 8686-8696.
Chemical & Engineering News Highlight

DeNap, J. B.; Thomas, J. R.; Musk, D. J.; Hergenrother, P. J. "Combating Drug-Resistant Bacteria: Small Molecule Mimics of Plasmid Incompatibility as Antiplasmid Compounds" J. Am. Chem. Soc. 2004, 126, 15402-15404.

Paul J. Hergenrother

Department of Chemistry

University of Illinois

270 Roger Adam Lab

600 South Mathews Avenue

Urbana, IL 61801


(217)333-0363
Fax: (217)244-8024
hergenro@uiuc.edu
Hergenrother Group

Photo of Paul J. Hergenrother
Chemistry at Illinois University of Illinois at Urbana-Champaign