Liqiang Chen, PhD

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 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.

• Ding, R.; Edwards, T. C.; Goswami, P.; Wilson, D. J.; Dreis, C. D.; Ye, Y.; Geraghty, R. J.;* Chen, L.* p97 Inhibitors possessing antiviral activity against SARS-CoV-2 and low cytotoxicity. Pharmaceuticals 2025, 18, 131.

• Ai, T.; Wilson, D. J.; Chen, L.* 5-((3-Amidobenzyl)oxy)nicotinamides as SIRT2 inhibitors: A study of constrained analogs. Molecules 2023, 28, 7655.

• Zhang, Q.; Tang, W.; Stancanelli, E.; Jung, E.; Syed, Z.; Pagadala, V.; Saidi, L.; Chen, C. Z.; Gao, P.; Xu, M.; Pavlinov, I.; Li, B.; Huang, W.; Chen, L.; Liu, J.; Xie, H.; Zheng, W.; Ye, Y. Host heparan sulfate promotes ACE2 super-cluster assembly and enhances SARS-CoV-2-associated syncytium formation. Nat. Commun. 2023, 14, 5777.

• Jung, E.; Soto-Acosta, R.; Xie, J.; Wilson, D. J.; Dreis, C. D.; Majima, R.; Edwards, T. C.; Geraghty, R. J.; Chen, L.* Bisubstrate inhibitors of Severe Acute Respiratory Syndrome Coronavirus‑2 Nsp14 methyltransferase. ACS Med. Chem. Lett. 2022, 13, 1477-1484.

• Jung, E.; Soto-Acosta, R.; Geraghty, R. J.; Chen, L.* Zika virus inhibitors based on a 1,3-disubstituted 1H-pyrazolo[3,4-d]pyrimidine-amine scaffold. Molecules 2022, 27, 6109.

• Soto-Acosta, R.; Jung, E.; Qiu, L.; Wilson, D. J.; Geraghty, R. J.;* Chen, L.* 4,7-Disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs as antiviral agents against flaviviruses and human coronavirus. Molecules 2021, 26, 3779.

• Ding, R.; Wilson, D. J.; Chen, L.* Synthesis of macrocyclic α-ketoamide as a selective and reversible immunoproteasome inhibitor. Med. Chem. Res. 2021, 30, 410-420.

• Wang, Y.; Soto-Acosta, R.; Ding, R.; Chen, L.;* Geraghty, R. J.* Anti-HCMV activity by an irreversible p97 inhibitor LC-1310. Med. Chem. Res. 2021, 30, 440-448.

• Ding, R.; Zhang, T.; Wilson, D. J.; Xie, J.; Williams, J.; Xu, Y.; Ye, Y.; Chen, L.* Discovery of irreversible p97 inhibitors. J. Med. Chem. 2019, 62, 2814-2829.

• Mooneyham, A.; Iizuka, Y.; Yang, Q.; Coombes, C.; McClellan, M.; Shridhar, V.; Emmings, E.; Shetty, M.; Chen, L.; Ai, T.; Meints, J.; Lee, M. K.; Gardner, M.; Bazzaro, M. UNC-45A Is a novel microtubule-associated protein and regulator of paclitaxel sensitivity in ovarian cancer cells. Mol. Cancer Res. 2019, 17, 370-383.

• Ai, T.; Willett, R.; Williams, J.; Ding, R.; Wilson, D. J.; Xie, J.; Kim, D. H.; Puertollano, R.; Chen, L.* N-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides: Antiproliferative activity and effects on mTORC1 and autophagy. ACS Med. Chem. Lett. 2017, 8, 90-95.

• Ai, T.; Wilson, D. J.; More, S. S.; Xie, J.; Chen, L.* 5-((3-Amidobenzyl)oxy)nicotinamides as sirtuin 2 inhibitors. J. Med. Chem. 2016, 59, 2928-2941.

• Ding, R.; Zhang, T.; Xie, J.; Williams, J.; Ye, Y.; Chen, L.* Eeyarestatin I derivatives with improved aqueous solubility. Bioorg. Med. Chem. Lett. 2016, 26, 5177-5181.

• Ai, T.; Qiu, L.; Xie, J.; Geraghty, R. J.; Chen, L.^* Design and synthesis of an activity-based protein profiling probe derived from cinnamic hydroxamic acid. Bioorg. Med. Chem. 2016, 24, 686-692.

• Vogel, R. I.; Pulver, T.; Heilmann, W.; Mooneyham, A.; Mullany, S.; Zhao, X.; Shahi, M.; Richter, J.; Klein, M.; Chen, L.; Ding, R.; Konecny, G.; Kommoss, S.; Winterhoff, B.; Ghebre, R.; Bazzaro, M. USP14 is a predictor of recurrence in endometrial cancer and a molecular target for endometrial cancer treatment. Oncotarget 2016, 7, 30962-30968.

• Yun, Y. S.; Kim, K. H.; Tschida, B.; Sachs, Z.; Noble-Orcutt, K. E.; Moriarity, B. S.; Ai, T.; Ding, R.; Williams, J.; Chen, L.; Largaespada, D.; Kim, D. H. mTORC1 coordinates protein synthesis and immunoproteasome formation via PRAS40 to prevent accumulation of protein stress. Mol. Cell 2016, 61, 625-639.

• Alhazzazi, T. Y.; Kamarajan, P.; Xu, Y.; Ai, T.; Chen, L.; Verdin, E.; Kapila, Y. L. A novel sirtuin-3 inhibitor, LC-0296, inhibits cell survival and proliferation, and promotes apoptosis of head and neck cancer cells. Anticancer Res. 2016, 36, 49-60.

• Preyat, N.; Rossi, M.; Kers, J; Chen, L.; Bertin, J.; Gough, P. J.; Le Moine, A.; Rongvaux, A.; Van Gool, F.; Leo, O. Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner. Cell Death Differ. 2016, 23, 29-40.

• Ai, T.; Xu, Y.; Qiu, L.; Geraghty, R. J.; Chen, L.^* Hydroxamic acids block replication of hepatitis C virus. J. Med. Chem. 2015, 58, 785-800.

• Cui, H.; Kamal, Z.; Ai, T.; Xu, Y.; More, S. S.; Wilson, D. J.; Chen, L.^* Discovery of potent and selective sirtuin 2 (SIRT2) inhibitors using a fragment-based approach. J. Med. Chem. 2014, 57, 8340-8357.

• 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.

• 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. Collection Symposium Series 2008, 10 (Chemistry of Nucleic Acid Components), 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.

• 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 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, p.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.

Research Funding Grants

Active

• R01DK132781A1 (Gradilone)                            02/01/2023 – 01/31/2027
  National Institutes of Health
  Primary Cilia loss in tumor cells; the interplay with the autophagy machinery
  The overall objective is to explore the mechanisms of ciliary loss in tumor cells with a focus on how the autophagy machinery is targeted to the resorption of this organelle. One goal is to assess dual inhibitors of autophagy and HDAC6 as a potential treatment of cholangiocarcinoma.
  Role: Co-I (PI: Sergio Gradilone)
• R21AI166065A1                                        06/15/2022 – 05/31/2024
  National Institutes of Health
  Bi-substrate inhibitors of SARS-CoV-2 Nsp14 methyltransferase
  The goal is to develop inhibitors of SARS-CoV-2 Nsp14 methyltransferase as antiviral agents that are suitable for proof-of-concept study in SARS-CoV-2 animal models.
  Role: PI
   

Completed

• R21AI151427                                        02/01/2020 – 01/31/2022
  National Institutes of Health
  Optimizing Zika NS5 methyltransferase inhibitors
  The goal is to develop inhibitors of Zika virus NS5 methyltransferase as antiviral agents that are suitable for proof-of-concept study in ZIKV animal models.
  Role: PI
• W81XWH-19-1-0069 (Yu)                             08/01/2019 – 07/31/2021
  USAMRAA, Department of Defense
  Exploiting SIRT2 for Breast Cancer Therapy
  The overall goal of this project is to determine the functional significance of SIRT-mediated deacetylation of MRE11 in the DNA damage response in breast cancer and characterize novel SIRT2 inhibitors and determine the synthetic lethal context for which they may be used for breast cancer therapy.
  Role: Co-I (PI: David Yu)
• Chainbreaker GOpher A Cure Awards (Gradilone)        07/01/2019 – 06/30/2020
  Masonic Cancer Center, University of Minnesota
  Ciliomax: Development of a dual inhibitor for ciliary restoration in tumor cells
  This proposal is to discover dual inhibitors of autophagy and HDAC6 and evaluate these dual inhibitors as a potential treatment of cholangiocarcinoma.
  Role: Co-PI (PI: Sergio Gradilone)
• Research Development and Seed Grant                    07/01/2014 – 06/30/2016
  Center for Drug Design, University of Minnesota
  Optimization of Sirtuin 2 inhibitors to target Parkinson’s disease
  This proposal seeks to explore optimized SIRT2 inhibitors as novel Parkinson’s disease (PD) therapeutics.
  Role: PI
• Research Development and Seed Grant                    07/01/2012 – 06/30/2014
  Center for Drug Design, University of Minnesota
  Inhibition of Sirtuin 2 as a potential treatment of Parkinson’s disease
  This proposal aims to discover novel chemotypes as potent and selective SIRT2 inhibitors and to explore them as Parkinson’s disease (PD) therapeutics.
  Role: PI
   

Patents

• Chen, L.; Geraghty, R. J.; Jung, E. SARS-CoV-2 Nsp14 methyltransferase inhibitors. International patent application No. PCT/US2023/023237.
• Chen, L.; Ai, T.; More, S. Therapeutic Compounds. US Patent 9,951,019.
• Chen, L.; Ai, T. Anticancer Compounds. US Patent 10,357,477.
• 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.