Liqiang Chen, Ph.D.

Assistant Professor, Center for Drug Design 
Assistant Director, Center for Drug Design

Contact information 

Office: 7-158 Phillips Wangensteen
Phone: 612-624-2575
Fax: 612-625-8154
E-mail: chenx462@umn.edu

Education

B.S., Xiamen University, China, 1991
Ph.D., University of Iowa, 2002

Our research is centered on the pharmacological modulation of enzymes involved in the de novo biosynthesis, utilization and recycling of nicotinamide adenine dinucleotide (NAD).  Generally considered a key player in redox reactions, NAD has also been involved in a wide array of cellular processes, including signal transduction, protein modifications, and DNA repair.  Because many NAD-processing enzymes are implicated in various medical conditions, they have been proposed as promising targets for the treatments of cancer, infection, metabolic and age-related diseases.

We have been interested in a family of enzymes named histone deacetylase (HDAC), which catalyzes the deacetylation of the acetyl lysine residue on histone tails.  There are 18 members of human HDAC which can be divided into four classes.  Class I, II and IV HDACs require zinc metal whereas Class III HDACs, which are named sirtuins, are NAD-dependent.  Counteracting histone acetyltransferase (HAT), HDAC controls the histone acetylation level, structural modification of chromatin, and subsequent regulation of genes that are implicated in cell growth, proliferation, and differentiation.  Furthermore, many non-histone proteins have been identified as HDAC substrates.  Numerous studies have demonstrated that inhibitions of HDAC offer therapeutic benefits.

Applying the principles of fragment- and structure-based drug design, we are currently investigating novel structural templates for the discovery of sirtuin inhibitors.  Our strategy is to design, synthesize and screen small fragments with limited structural features.  Preliminary biological evaluations of these fragments allow for an expeditious exploration of diverse chemical structures, and provide useful information about the protein-ligand interactions.  Subsequent chemical modifications, guided by the observed structure-activity relationship (SAR) and computational modeling, are aimed to optimize of the potency and potential selectivity among sirtuin isoforms.  Promising compounds are further assessed for their pharmacokinetics (PK) parameters and in vivo efficacy.  Our goal, through close collaborations within an interdisciplinary team of medicinal chemists, computational chemists, biochemists, and molecular biologists, is to identify potent and selective sirtuin inhibitors with desired pharmacological properties.

Selected Publications

Chen, L.; Wilson, D. J.; Labello, N. P.; Jayaram, H. N.; Pankiewicz, K. W.  Mycophenolic acid analogues with a modified metabolic profile.  Bioorg. Med. Chem. 2008, 16, 9340-9345.

Chen, L.; Petrelli, R.; Olesiak, M.; Wilson, D. J.; Labello, N. P.; Pankiewicz, K. W.  Bis(sulfonamide) isosters of mycophenolic adenine dinucleotide analogues: Inhibition of inosine monophosphate dehydrogenase.  Bioorg. Med. Chem. 2008, 16, 7462-7469.

Chen, L.; Petrelli, R.; Felczak, K; Gao, G.; Bonnac, L.; Yu, J. S.; Bennett, E. M.; Pankiewicz, K. W.  Nicotinamide adenine dinucleotide based therapeutics.  Curr. Med. Chem. 2008, 15, 650-670.

Chen, L.; Wilson, D.; Jayaram, H. N.; Pankiewicz, K. W.  Dual inhibitors of IMP-dehydrogenase and histone deacetylases for cancer treatment.  J. Med. Chem.2007, 50, 6685-6691.

Chen, L.; Gao, G.; Felczak, K.; Bonnac, L.; Patterson, S. E.; Wilson, D.; Bennett, E.; Jayaram, H. N.; Hedstrom, L.; Pankiewicz, K. W.  Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues.  J. Med. Chem.2007, 50, 5743-5751.

Bonnac, L.; Gao, G. Y.; Chen, L.; Felczak, K.; Bennett, E. M.; Xu, H.; Kim, T.; Liu, N.; Oh, H.; Tonge, P. J.; Pankiewicz, K. W.  Synthesis of 4-phenoxybenzamide adenine dinucleotide as NAD analogue with inhibitory activity against enoyl-ACP reductase (InhA) of Mycobacterium tuberculosis.  Bioorg. Med. Chem. Lett. 2007, 17, 4588-4591.

Witter, D. J.; Belvedere, S.; Chen, L.; Secrist, J. P.; Mosley, R. T.; Miller, T. A.  Benzo[b]thiophene-based histone deacetylase inhibitors.  Bioorg. Med. Chem. Lett. 2007, 17, 4562-4567.

Chen, L.; Pankiewicz, K. W.  Recent development of IMP dehydrogenase inhibitors for the treatment of cancer.  Curr. Opin. Drug Discov. Devel. 2007, 10, 403-412.

Chen, L.; Gao, G.; Bonnac, L.; Wilson, D. J.; Bennett, E. M.; Jayaram, H. N.; Pankiewicz, K. W.  Methylenebis(sulfonamide) linked nicotinamide adenine dinucleotide analogue as an inosine monophosphate dehydrogenase inhibitor.  Bioorg. Med. Chem. Lett. 2007,17, 3152-3155.

Bonnac, L.; Chen, L.; Pathak, R.; Gao, G.; Qian, M.; Bennett, E.; Felczak, K.; Kullberg, M.; Patterson, S. E.; Mazzola, F.; Magni, G.; Pankiewicz, K. W.  Probing binding requirements of NAD kinase with modified substrate (NAD) analogues.  Bioorg. Med. Chem. Lett. 2007,17, 1512-1515.

Zou, G.; Puig-Basagoiti, F.; Zhang, B.; Qing, M.; Chen, L.;Pankiewicz, K. W.; Felczak, K.; Yuan, Z.; Shi, P. Y. A single-amino acid substitution in West Nile virus 2K peptide between NS4A and NS4B confers resistance to lycorine, a flavivirus inhibitor. Virology 2009, 384, 242-252.

A detailed publication list is also available.