Liqiang Chen, PhD

Assistant Professor, Center for Drug Design (CDD)

Liqiang Chen

Contact Info

chenx462@umn.edu

Office Phone 612-624-2575

Fax 612-625-8154

Office Address:
7-214 Phillips-Wangensteen Building
516 Delaware Street SE
Minneapolis, MN-55455

Mailing Address:
MMC 204
312 Church St. SE
Minneapolis, MN 55455

Assistant Professor, Center for Drug Design (CDD)


PhD, University of Iowa (Organic Chemistry), 2002

Xiamen University (Chemistry), 1991

Summary

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.

Research

Research Summary/Interests

Research Interests

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.

Research Projects

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.

Patents

  • Pankiewicz, K. W.; Chen, L.; Vince, R. Anticancer Agents. WO/2009/018344.
  • Shi, P-Y.; Puig-Basagoiti, F.; Pankiewicz, K. W.; Felczak, K.; Chen, L. Anti-flavivirus Therapeutic. WO/2010/022238 and US 2011/0212986 A1.

Publications

  • Ai, T.; Xu, Y.; Qiu, L.; Geraghty, R. J.; Chen, L. Hydroxamic acids block replication of hepatitis C virus. J. Med. Chem. 2014, published online (DOI: 10.1021/jm501330g)
  • Ai, T.; Cui, H.; Chen, L.* Multi-targeted histone deacetylase inhibitors in cancer therapy. Curr. Med. Chem. 2012, 19, 475-487.
  • Chen, L. Medicinal chemistry of sirtuin inhibitors. Curr. Med. Chem.2011, 18, 1936-1946.
  • Felczak, K.; Chen, L.; Wilson, D.; Williams, J.; Vince, R.; Petrelli, R.; Jayaram, H. N.; Kusumanchi, P.; Kumar, M.; Pankiewicz, K. W. Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: targeting the pyrophosphate binding sub-domain. Bioorg. Med. Chem. 2011, 19, 1594-1605.
  • Chen, L.*; Petrelli, R.; Gao, G.; Wilson, D. J.; McLean, G. T.; Jayaram, H. N.; Sham, Y. Y.; Pankiewicz, K. W. Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylase based on a cinnamic hydroxamic acid core structure. Bioorg. Med. Chem. 2010, 18, 5950-5964.
  • Chen, L.*; Wilson, D. J.; Xu, Y.; Aldrich, C. C.; Felczak, K.; Sham, Y. Y.; Pankiewicz, K. W. Triazole-linked inhibitors of inosine monophosphate dehydrogenase from human and Mycobacterium tuberculosis. J. Med. Chem. 2010, 53, 4768-4778.
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  • Petrelli, R.; Sham, Y. Y.; Chen, L.; Felczak, K.; Bennett, E. M.; Aldrich, C.; Wilson, D. J.; Yu, J. S.; Cappellacci, L.; Franchetti, P.; Grifantini, M.; Mazzola, F.; Di Stefano, M.; Magni, G.; Pankiewicz, K. W. Selective inhibition of NAD kinase by dinucleoside disulfide NAD mimics. Bioorg. Med. Chem. 2009, 17, 5656-5664.
  • 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.
  • 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.
  • Neres, J.; Labello, N. P.; Somu, R. V.; Boshoff, H. I.; Wilson, D. J.; Vannada, J.; Chen, L.; Barry, C. E. III; Bennett, E. M.; Aldrich, C. C. Inhibition of siderophore biosynthesis in Mycobacterium tuberculosis with nucleoside bisubstrate analogues: Structure-activity relationships of the nucleobase domain of 5?-O-[N-(salicyl)sulfamoyl]adenosine. J. Med. Chem. 2008, 51, 5349-5370.
  • 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; Olesiak, M.; Bennett, E. M.; Magni, G.; Pankiewicz, K. W. Novel cofactor-type inhibitors of NAD-dependent enzymes. NAD-based therapeutics. Collect. Symp. Ser. 2008, 10, 71-79.
  • 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.

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  • 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.

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  • 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 Discovery Dev. 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. F.; Gao, G. Y.; Chen, L.; Patterson, S. E.; Jayaram, H. N.; Pankiewicz, K. W. Efficient synthesis of benzamide riboside, a potential anticancer agent. Nucleosides Nucleotides Nucleic Acids 2007, 26, 1249-1253.
  • 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.
  • Rejman, D.; Olesiak, M.; Chen, L.; Patterson, S. E.; Wilson, D.; Jayaram, H. N.; Hedstrom, L.; Pankiewicz, K. W. Novel methylenephosphophosphonate analogues of mycophenolic adenine dinucleotide. Inhibition of inosine monophosphate dehydrogenase. J. Med. Chem.2006, 49, 5018-5022.
  • Chen, L.; Rejman, D.; Bonnac, L.; Pankiewicz, K. W.; Patterson, S. E. Nucleoside-5'-phosphoimidazolides: Reagents for facile synthesis of dinucleotide pyrophosphates. Curr. Protoc. Nucleic Acid Chem. 2006, 13.4.1-13.4.10.
  • Chen, L.; Wiemer, D. F. Synthesis of a carbon analog of N-acetyl mannosamine via acetolysis on a relatively stable ozonide. J. Org. Chem. 2002, 67, 7561-7564.
  • Chen, L.; Wiemer, D. F. Tandem reduction-reductive alkylation of azido sugars. Tetrahedron Lett. 2002, 43, 2705-2708.