个人简介
B.Sc., 1991, Central China Normal University, Wuhan, China (Chemistry)
M.Sc., 1994, Nankai University, Tianjin, China (Organic Chemistry)
Ph.D., 1997, Nankai University, Tianjin, China (Organic Chemistry)
Postdoctoral Fellow, 1999-2001, Department of Chemistry, University of Virginia
Postdoctoral Fellow, 2001-2003, Drug Discovery Program, Georgetown University Medical Center
Residential School on Medicinal Chemistry, 2009, Drew University, Madison, NJ
研究领域
My research interests are broadly based on the interface of synthetic organic chemistry and medicinal chemistry, and in particular on the drug discovery of bioactive molecules to probe biological systems or act as potential therapeutic agents in neuroscience, cancer/inflammation, infectious diseases, and other human conditions. With this general idea in mind, and in active collaboration with other biologists and pharmacologists, my group is dedicated to establish a strong and creative research program that applies state-of-the-art chemical approaches to biological problems impacting diagnosis, prevention and treatment of human diseases.
One of our current efforts is focused on design and synthesis of small molecules for probing function and development of pharmacological tools for understanding the workings of the brain and that of novel therapies for central nervous system (CNS) disorders such as drug abuse and addiction, depression, schizophrenia, pain, and neurodegenerative diseases. The proposed projects in this area include the identification, characterization and optimization of allosteric modulators, bitopic ligands, and inverse agonists of 5-HT2C receptor, neuromedin U receptor 2 (NMUR2) ligands, as well as AMPA receptor positive allosteric modulators for preventing neuroapoptosis and opioid use disorder pharmacotherapy. We are also working on the discovery of dopamine D1 biased ligands, orphan GPCR (oGPCR) including GPR52 ligands, DeltaFosB inhibitors, neurexin modulators, and FGF14/Nav1.6 channel complex protein-protein interaction inhibitors as CNS probes and potential therapeutics.
Another line of research development centers on the establishment of novel chemical libraries aiming at mechanism-based or lead compound-based drug discovery for cancer/inflammation, particularly by targeting Bcl-2 family proteins and apoptosis pathways, transcription factors as well as epigenetic therapy with the aid of molecular docking and chemical synthesis. Specifically, we are developing Bax activators, BH4 domain antagonists of Bcl2, Survivin inhibitors, orally bioavailable STAT3 inhibitors, glycolysis inhibitors, AP-1 inhibitors, KLF5 inhibitors, KRAS plasma membrane localization inhibitors, cystathionine-β-synthase (CBS) inhibitors, SIRT6 activators, TRIM28 inhibitors, CDK9 inhibitors, MYC inhibitors, PRMT5 inhibitors, BRD4 inhibitors and relevant protein degraders as a new class of preventive/therapeutic agents for various human cancers including brain tumors, breast cancer, lung cancer, head/neck cancer, colorectal cancer, gastric cancer, prostate cancer, and pancreatic cancer as well as inflammation (e.g. airway remodeling and inflammatory bowel diseases).
Our research efforts on developing chemical probes include design and synthesis of small molecules targeting EPAC, which are exchange proteins directly activated by cAMP including cAMP-regulated guanine nucleotide exchange factors. These EPAC inhibitors together with other mechanism-based therapeutics have also demonstrated as promising therapeutics for a variety of indications including infectious diseases. Utilizing structure-based and fragment-based drug design by collaborating with viral research biologists, we are developing novel small molecules as therapeutic candidates targeting viral proteins such as dengue viral NS4B, flavivirus NS2B-NS3 protease and RNA-dependent RNA polymerase (RdRp). Meanwhile, we are also developing novel target-based small molecules as therapeutics to epigenetically silencing HIV or latency reversing agents for HIV eradication or HIV/TB co-infection. Last but not least, we are also working on natural product-inspired diversity-oriented synthesis that may lead to exciting potentials for discovery of novel targets and drug candidates.
近期论文
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E. A. Wold, E. J. Garcia, C. T. Wild, J. M. Miszkiel, C. A. Soto, J. Chen, K. Pazdrak, R. G. Fox, N. C. Anastasio, K. A. Cunningham, J. Zhou. Discovery of 4-Phenylpiperidine-2-Carboxamide Analogues as Serotonin 5-HT2C Receptor Positive Allosteric Modulators with Enhanced Drug-Like Properties. J. Med. Chem. 2020, In press. DOI: 10.1021/acs.jmedchem.9b01953. PMID: 32567857
Z. Liu, H. Chen, P. Wang, Y. Li, E. A. Wold, P. G. Leonard, S. Joseph, A. R. Brasier, B. Tian, J. Zhou. Discovery of Orally Bioavailable Chromone Derivatives as Potent and Selective BRD4 Inhibitors: Scaffolding Hopping, Optimization and Pharmacological Evaluation. J. Med. Chem. 2020, 63 (10), 5242-5256. PMID: 32255647. [Journal Cover Article]
Y. Li, Z. Liu, G. Aglyamova, J. Chen, H. Chen, M. Bhandari, M. A. White, G. Rudenko, J. Zhou. Discovery of phenanthridine analogues as novel chemical probes disrupting the binding of DNA to ΔFosB homodimers and ΔFosB/JunD heterodimers. Bioorg. Med. Chem. Lett., 2020, 30 (16), 127300. https://doi.org/10.1016/j.bmcl.2020.127300.
P. Wang, U. Luchowska-Stańska, H. Chen, Z. Liu, J. Wiejak, P. Whelan, D. Morgan, E. Lochhead, G. Barker, H. Rehmann, S. J. Yarwood, J. Zhou. Synthesis and Biochemical Evaluation of Non-Cyclic Nucleotide Exchange Protein Directly Activated by cAMP1 (EPAC1) Regulators. J. Med. Chem. 2020, 63 (10), 5159-5184. PMID: 32340447.
J. Xu, J. Berastegui-Cabrera, H. Chen, J. Pachón-Díaz, J. Zhou* (Co-Corresponding author), Javier Sánchez-Céspedes. Structure-Activity Relationship Studies on Diversified Salicylamide Derivatives as Potent Inhibitors of Human Adenovirus Infection. J. Med. Chem. 2020, 63 (6), 3142-3160. PMID: 32045239. [Journal Cover Article]
J. Xu, P.-Y. Shi, H. Li, J. Zhou. Broad Spectrum Antiviral Agent Niclosamide and Its Therapeutic Potential. ACS Infectious Diseases, 2020, 6 (5), 909-915. PMID: 32125140. PMCID: PMC7098069.
H. Shao, H. Mohamed, S. Boulton, J. Huang, P. Wang, H. Chen, J. Zhou, U. Luchowska-Stańska, N. Jentsch, A. Armstrong, J. Magolan, S. Yarwood; G. Melacini. Mechanism of Action of an EPAC1-Selective Competitive Partial Agonist. J. Med. Chem. 2020, 63 (9), 4762-4775. PMID: 32297742.
A. R. Brasier*, J. Zhou*. Validation of the epigenetic reader bromodomain-containing protein 4 (BRD4) as a therapeutic target for treatment of airway remodeling. Drug Discov. Today, 2020, 25 (1), 126-132. PMID: 31733396. PMCID: PMC6980722.
J. Xu, X. Xie, H. Chen, J. Zou, Y. Xue, N. Ye, P.Y. Shi, J. Zhou. Design, synthesis and biological evaluation of spiropyrazolopyridone derivatives as potent dengue virus inhibitors. Bioorg. Med. Chem. Lett., 2020, 30 (11), 127162. PMID: 32247736.
C. T. Wild, J. M. Miszkiel, E. A. Wold, C. A. Soto, C. Ding, R. M. Hartley, M. A. White, N. C. Anastasio, K. A. Cunningham, and J. Zhou. Design, Synthesis and Characterization of 4-Undecylpiperidine-2-Carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT2C Receptor. J. Med. Chem. 2019, 62 (1), 288-305. PMID: 29620897. [Paper of a Special Issue on Allosteric Modulators of Drug Targets]
E. A. Wold, C. Wild, K. A. Cunningham, J. Zhou. Targeting the 5-HT2C Receptor in Biological Context and the Current State of 5-HT2C Receptor Ligand Development. Curr. Top. Med. Chem., 2019, 19 (16), 1381-1398. PMID: 31288724.
N. Ye, Q. Xu, W. Li, P. Wang, J. Zhou. Recent Advances in Developing K-Ras Plasma Membrane Localization Inhibitors. Curr. Top. Med. Chem. 2019, 19 (23), 2114-2127. PMID: 31475899.
J. Xu, X. Xie, N. Ye, J. Zou, H. Chen, M. A. White, P. Y. Shi, J. Zhou. Design, Synthesis, and Biological Evaluation of Substituted 4,6-Dihydrospiro[[1,2,3]triazolo[4,5-b]pyridine-7,3'-indoline]-2',5(3H)-dione Analogues as Potent NS4B Inhibitors for the Treatment of Dengue Virus Infection. J. Med. Chem., 2019, 62 (17):7941-7960. PMID: 31403780.
P. Wang, D. E. Felsing, H. Chen, S. R. Raval, J. A. Allen, J. Zhou. Synthesis and Pharmacological Evaluation of Non-catechol G Protein Biased and Unbiased Dopamine D1 Receptor Agonists. ACS Med. Chem. Lett., 2019, 10 (5), 792-799. PMCID: PMC6511950. [Cover paper of the journal; F1000Prime Recommended Article].
Q. Niu, Z. Liu, F. Liu, E. Alamer, X. Fan, H. Chen, J. Endsley, B. B. Gelman, B. Tian, J. H. Kim, N. L. Michael, M. L. Robb, J. Ananworanich, J. Zhou* (Co-Corresponding author), H. Hu*. Structure-guided drug design identifies a BRD4-selective small molecule that suppresses HIV. J. Clin. Investig. (JCI), 2019, 129 (8), 3361-3373. PMID: 31329163.
B. Tian, K. Hosoki, Z. Liu, J. Yang, Y. Zhao, H. Sun, J. Zhou, E. Rytting, L. Kaphalia, W. J Calhoun, S. Sur, A. R Brasier. Mucosal Bromodomain-Containing Protein 4 (BRD4) Regulates Aeroallergen-induced Airway Remodeling and Sensitization. J. Allergy Clin. Immunol., 2019, 143 (4), 1380-1394.e9. PMID: 30321559.
G. Liu, T. Yin, H. Kim, C. Ding, Z. Yu, H. Wang, H. Chen, R. Yan, E. A. Wold, H. Zou, X. Liu, Y. Ding, Q. Shen, J. Zhou. Structure-Activity Relationship Studies on Bax Activator SMBA1 for the Treatment of ER-Positive and Triple-Negative Breast Cancer. Eur. J. Med. Chem., 2019, 178, 589-605. PMID: 31220676.
J. Xu, M. E., Pachón-Ibáñez, T. Cebrero-Cangueiro, H. Chen, J. Sánchez-Céspedes, J. Zhou. Discovery of niclosamide and its O-alkylamino-tethered derivatives as potent antibacterial agents against carbapenemase-producing and/or colistin resistant Enterobacteriaceae isolates. Bioorg. Med. Chem. Lett., 2019, 29 (11), 1399-1402. PMID: 30954430.
B. Tian, Z. Liu, J. Litvinov, R. Maroto, M. Jamaluddin, E. Rytting, I. Patrikeev, L. Ochoa, G. Vargas, M. Motamedi, B. T. Ameredes, J. Zhou, A. R Brasier. Efficacy of Novel Highly Specific Bromodomain-Containing Protein 4 (BRD4) Inhibitors in Innate Inflammation-Driven Airway Remodeling. Am. J. Respir. Cell Mol. Biol. 2019, 60 (1), 68-83. PMID: 30153047.
J. Zhou*(Co-Corresponding author), K. A. Cunningham*. Positive Allosteric Modulation of the 5-HT2C Receptor: Implications for Neuropsychopharmacology and Neurotherapeutics. Neuropsychopharmacology, 2019, 44 (1), 230-231. PMID: 30202047. PMCID: PMC6235849
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