Chemistry at Illinois University of Illinois at Urbana-Champaign

Paul J. Hergenrother

Kenneth Rinehart Jr. Endowed Chair in
natural products chemistry
Professor of chemistry
Affiliate, Department of Biochemistry

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 organic compounds to identify novel cellular targets that can be exploited in the treatment of diseases including cancer, degenerative disorders, and drug-resistant bacteria. The compounds we discover 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.

Synthesis of Complex and Diverse Compounds from Natural Products.

High-throughput screening remains the backbone of most drug discovery efforts, yet compounds in screening collections are typically simple molecules and are in screening collections because they were easy to synthesize. We have developed a new strategy for the rapid construction of complex and diverse compounds: Starting from abundant natural products, in five or fewer chemical steps these complex molecules are diversified to compounds that retain the complexity of natural products but that are very different from the parent structures. We have generated thousands of novel compounds through this “Complexity-to-Diversity” (CtD) method, compounds that now serve as starting points for future biological discoveries.

Novel anti-cancer targets.

A “personalized” cancer drug is one that exploits a molecular defect specifically present in the cancer cells of a patient. Our objective is to identify both novel biological targets for personalized medicine, and also novel compounds. One of our leading success stories in this area is the discovery that direct activation of procaspase-3 is a powerful and selective anticancer strategy, and the discovery of the first procaspase-activating compound, PAC-1. The anticancer activities of PAC-1 have now been well-documented and this compound is rapidly progressing toward human clinical trials. Another success story has been the identification of the natural product deoxynyboquinone (DNQ) as a powerful and personalized anticancer agent, in this case specific for those cancers that overexpress the enzyme NQO1. We are actively involved in the identification of many other personalized compounds and targets for the treatment of cancer.

Novel targets for drug-resistant bacteria.

Every year 90,000 people in the U.S. alone die from bacterial infections they acquire at hospitals, caused by pathogens that are resistant to multiple antibiotics. We are actively involved in several strategies to identify compounds that specifically kill drug-resistant bacteria.

Publications

Hicklin, R. W.; Lopez-Silva, T. L.; Hergenrother, P. J. “Synthesis of Bridged Oxa-Fenestranes from Pleuromutilin” Angew. Chem. Int. Ed. 2014, 53, 9880-9883.

Botham, R. C.; Fan, T. M.; Im, I.; Borst, L. B; Dirikolu, L.; Hergenrother, P. J. “Dual Small-Molecule Targeting of Procaspase-3 Dramatically Enhances Zymogen Activation and Anticancer Activity” J. Am. Chem. Soc. 2014, 136, 1312-1319.

Rafferty, R. J.; Hicklin, R. W.; Maloof, K. A., Hergenrother, P.J. “Synthesis of Complex and Diverse Compounds through Ring Distortion of Abietic Acid” Angew. Chem. 2014, 53, 220-224.

Parkinson, E. I.; Bair, J. S.; Cismesia, M.; Hergenrother, P. J. “Efficient NQO1 Substrates are Potent and Selective Anticancer Agents” ACS Chem. Biol. 2013, 8, 2173-2183.

Granger, B. A.; Jewett, I, T.; Butler, J. D.; Hua, B.; Knezevic, C. E.; Parkinson, E. I.; Hergenrother, P. J.; Martin, S. F. “Synthesis of (+/-)-Actinophyllic Acid and Analogs:  Applications of Cascade Reactions and Diverted Total Synthesis” J. Am. Chem. Soc. 2013, 135, 12984-12986.

Huigens, R. W.; Morrison, K. C.; Hicklin, R. W.; Flood, T. A.; Richter, M. F.; Hergenrother, P. J. “A Ring Distortion Strategy to Construct Stereochemically Complex and Structurally Diverse Compounds from Natural Products” Nature Chem. 2013, 5, 195-202.

Dunstan, M. S.; Barkauskaite, E.; Lafite, P.; Knezevic, C. E.; Hergenrother, P. J.; Leys, D.; Ahel, I. “Structure and Mechanism of a Canonical Poly(ADP-Ribose) Glycohydrolase” Nature Comm. 2012, 3, 878.

Huang, X.; Dong, Y.; Bey, E. A.; Kilgore, J. A.; Bair, J. S.; Li, L.-S.; Patel, M.; Parkinson, E. I.; Wang, Y.; Williams, N. S.; Gao, J.; Hergenrother, P. J.; Boothman, D. A. “An NQO1 Substrate with Potent Antitumor Activity that Selectively Kills by PARP1-Induced Programmed Necrosis” Cancer Res. 2012, 72, 3038-3047.

Finch, K. E.; Knezevic, C. E.; Nottbohm, A. C.; Partlow, K. C. Hergenrother, P. J. “Selective Small Molecule Inhibition of Poly(ADP-Ribose) Glycohydrolase (PARG)” ACS Chem. Biol. 2012, 7, 563-570.

Williams, J. J.; Hergenrother, P. J. “Artificial Activation of Toxin-Antitoxin Systems as an Antibacterial Strategy” Trends Microbiol. 2012, 20, 291-298.

Hsu, D. C.; Roth, H. S.; West, D. C.; Botham, R. C.; Novotny, C. J.; Schmid, S. C.; Hergenrother, P. J. "Parallel Synthesis and Biological Evaluation of 837 Analogues of Procaspase-Activating Compound 1 (PAC-1)" ACS Combi. Sci. 2012, 14, 44-50.

Morrison, Karen C.; Hergenrother, P. J. "Whole Cell Microtubule Analysis by Flow Cytometry" Anal. Biochem. 2012, 420, 26-32.

Williams, J. J.; Halvorsen, E. M.; Dwyer, E. M.; DiFazio, R. M.; Hergenrother, P. J. "Toxin-Antitoxin (TA) Systems are Prevalent and Transcribed in Clinical Isolates of Pseudomonas aeruginosa and Methicillin-Resistant Staphylococcus aureus" FEMS Microbiol. Lett. 2011, 322, 41-50.

Granchi, C.; Roy, S.; Giacomelli, C.; Macchia, M.; Tuccinardi, T.; Martinelli, A.; Lanza, M.; Betti, L.; Giannaccini, G.; Lucacchini, A.; Funel, N.; Leon, L. G.; Giovannetti, E.; Peters, G. J.; Palchaudhuri, R.; Calvaresi, E. C.; Hergenrother, P. J.; Minutolo, F. "Discovery of N-Hydroxyindole-Based Inhibitors of Human Lactate Dehydrogenase Isoform A (LDH-A) as Starvation Agents Against Cancer Cells" J. Med. Chem. 2011, 54, 1599-1612.

Halvorsen, E. M.; Williams, J. J.; Bhimani, A. J.; Billings, E. A.; Hergenrother, P. J. "Txe, an Endoribonuclease of the Enterococcal Axe-Txe Toxin-Antitoxin System, cleaves mRNA and inhibits protein synthesis" Microbiology, 2011, 157, 387-397.

Palchaudhuri, R.; Hergenrother, P. J. "Transcript Profiling and RNA Interference as Tools to Identify Small Molecule Mechanisms and Therapeutic Potential" ACS Chem. Biol. 2011, 6, 21-33.

Hoyt, M.T.; Palchaudhuri, R.; Hergenrother, P. J. "Cribostatin 6 Induces Death in Cancer Cells Through a Reactive Oxygen Species (ROS)-Mediated Mechanism" Invest. New Drugs 2011, 29, 562-573.

Heeres, J. T.; Hergenrother, P. J. "High-Throughput Screening for Modulators of Protein-Protein Interactions: Use of Photonic Crystal Biosensors and Complementary Technologies" Chem. Soc. Rev. 2011, 40, 4398-4410.

Peterson, Q. P.; Hsu, D. C.; Novotny, C. J.; West, D. C.; Kim, D.; Schmit, J. M.; Dirikolu, L.; Hergenrother, P. J.; Fan, T. M. "Discovery and Canine Preclinical Assessment of a Nontoxic Procaspase-3 Activating Compound" Cancer Res.2010, 70, 7232-7241.

Leslie, B. J.; Holaday, C. R.; Nguyen, T.; Hergenrother, P. J. "Phenylcinnamides as Novel Antimitotic Agents" J. Med. Chem. 2010, 53, 3964-3972.

Bair, J. S.; Palchaudhuri, R.; Hergenrother, P. J. "Chemistry and Biology of Deoxynyboquinone, a Potent Inducer of Cancer Cell Death" J. Am. Chem. Soc.2010, 132, 5469-5478.

Peterson, Q. P.; Goode, D. R.; West, D. C.; Botham, R. C.; Hergenrother, P. J. "Preparation of the Caspase-3/-7 Substrate Ac-DEVD-pNA via Solution-Phase Peptide Synthesis" Nature Protocols 2010, 5, 294-302.

Peterson, Q.P.; Hsu, D.C.; Goode, D.R.; Novotny, C.J.; Totten, R.K.; Hergenrother, P.J. "Procaspase-3 Activation as an Anti-Cancer Strategy: Structure-Activity Relationship of PAC-1, and its Cellular Co-Localization with Caspase-3" J. Med. Chem. 2009, 52, 5721-5731.

Meyer, S.T.; Hergenrother, P.J. "Small Molecule Ligands for Bulged RNA Secondary Structures" Org. Lett. 2009, 11, 4052-4055.

Peterson, Q.P.; Goode, D.R.; West, D.C.; Ramsey, K.N.; Lee, J.J.Y.; Hergenrother, P.J. "PAC-1 Activates Procaspase-3 in vitro Through Relief of Zinc-Mediated Inhibition" J. Mol. Biol. 2009, 388, 144-158.

Thompson, C.M.; Quinn, C.A.; Hergenrother, P.J. "The Total Synthesis and Cytoprotective Properties of Dykellic Acid" J. Med. Chem. 2009, 52, 117-125.

Palchaudhuri, R.; Hergenrother, P. J. "Structure-Activity-Relationship of Triphenylmethylamides, Compounds that Potently Induce Apoptosis in Melanoma Cell Lines" Bioorg. Med. Chem. Lett. 2008, 18, 5888-5891.

Williams, J. J.; Hergenrother, P. J. "Exposing Plasmids as the Achilles' Heel of Drug-Resistant Bacteria" Curr. Opin. Chem. Biol. 2008, 12, 389-399.

Palchaudhuri, R.; Nesterenko, V.; Hergenrother, P. J. "The Complex Role of the Triphenylmethyl Motif in Anti-Cancer Compounds" J. Am. Chem. Soc. 2008, 130, 10274-10274.

Chan, L. C.; Pineda, M.; Heeres, J. T.; Hergenrother, P. J., Cunningham, B. T. “A General Method for Discovering Inhibitors of Protein-DNA Interactions Using Photonic Crystal Biosensors” ACS Chem. Biol. 2008, 3, 437-448.

Palchaudhuri, R.; Nesterenko, V.; Hergenrother, P. J. “The Complex Role of the Triphenylmethyl Motif in Anti-Cancer Compounds” J. Am. Chem. Soc. 2008, 130, 10274-10281.

Leslie, B. J.; Hergenrother, P. J. “Identification of the cellular targets of bioactive small organic molecules using affinity reagents” Chem. Soc. Rev. 2008, 37, 1347-1360 (review).

Goode, D. R.; Totten, R. K.; Heeres, J. T.; Hergenrother, P. J. “Identification of Promiscuous Small Molecule Activators in High-Throughput Enzyme Activation Screens” J. Med. Chem. 2008, 51, 2346-2349.

Thomas, J. R.; Hergenrother, P. J. “Targeting RNA with Small Molecules” Chem. Rev. 2008, 108, 1171-1224 (review).

Musk, D. J.; Hergenrother, P. J. “Chelated Iron Sources are Inhibitors of Psudomonas aeruginosa Biofilms and Distribute Efficiently in an in vitro Model of Drug Delivery to the Human Lung” J. Applied Microbiol. 2008, 105, 380-388.

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.

Awards

Highlights

Vanquish Oncology announces a multimillion dollar investment to move PAC-1 to clinical trials for human cancer patients. Read the article here.

On January 7, 2013 StemPar Sciences, Inc. (South San Francisco) announced the licensing of the DNQ family of anticancer compounds developed in the Hergenrother lab. Read the article here.

C&E News highlight of Hergenrother lab method to synthesize complex and diverse compounds from natural products. Read the C&E News article here.

Vanquich Oncology, Inc. founded to develop procaspase-3 activating compounds from the Hergenrother Lab. For more information, click here.

A compound discovered in the Hergenrother lab shows promise in a small Phase 1 clinical trial in pet dogs with lymphoma. Read more at the UIUC News Bureau

Peterson, Q.P.; Hsu, D.C.;Novotny, C.J.; West, D.C.;Kim, D.;Schmit, J.M.; Dirikolu, L.;Hergenrother, P.J.; Fan, T.M. &quotDiscovery and Canine Preclinical Assessment of a Nontoxic Procaspase-3 Activating Compound&quot Cancer Res. 2010,70,7232-7241.

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.

Chan, L. C.; Pineda, M.; Heeres, J. T.; Hergenrother, P. J., Cunningham, B. T. "A General Method for Discovering Inhibitors of Protein-DNA Interactions Using Photonic Crystal Biosensors" ACS Chem. Biol. 2008, 3, 437-448.
http://www.rsc.org/chemistryworld/News/2008/August/26080801.asp

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.

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.

Patents

Hergenrother, P. J.; Peterson, Q. P.; Hsu, D. C.; West, D. C.; Fan, T. M; Novotny, C. H. “Design, Synthesis and Evaluation of Procaspase Activating Compounds as Personalized Anti-Cancer Drugs” issued on July 15, 2014 as U.S. patent 8,778,945.

Zimmerman, S.C.; Hergenrother, P. J.; Wong, C.-H.; Peh, J. “Therapeutic Methods and Agents for Treating Myotonic Dystrophy issued on June 17, 2014 as U.S. patent 8,754,084.

Hergenrother, P. J.; Putt, K. S.; Peterson, Q. P.; Fako, V. “Compositions and Methods Including Cell Death Inducers and Procaspase Activation”  issued on November 26, 2013 as U.S. patent 8,592,584.

Hergenrother, P. J.; Nesterenko, V.; Putt, K. S.; Palchaudhuri, R. “Phosphorous-Containing Compounds Including Triphenylmethylphosphonate Esters for the Treatment of Melanoma and Other Cancers” issued on May 4, 2010 as U.S. patent 7,709,465.

Hergenrother, P. J.; Nesterenko, V.; Putt, K. S.; Allen, B. J.; Leslie, B.; Dothager, R. “Compounds and Methods for Treatment of Cancer and Modulation of Programmed Cell Death for Melanoma and Other Cancer Cells” issued Dec. 15, 2009 as U.S. Patent 7,632,972.

Schreiber, S. L.; MacBeath, G.; Koehler, A. K.; Hergenrother, P. J.; Depew, K. M. "Small Molecule Printing"  issued Nov. 30, 2004 as U.S. Patent 6,824,987.

Photo of Paul J. Hergenrother