Jun Liu, MS, PhD

Professional Titles

• Co-Director, Cancer Chemical and Structural Biology, Kimmel Comprehensive Cancer Center
• Director, Johns Hopkins Drug Library
• Director, ChemBioCORE
• Director, Drug Discovery CORE of the FAMRI Center of Excellence at Johns Hopkins

Primary Academic Title

Professor of Pharmacology and Molecular Sciences

Background

Centers and Institutes

• Basic Biomedical Sciences, Institute for
• Malaria Research Institute
• Sidney Kimmel Comprehensive Cancer Center

Videos

• Looking to Nature for New Medications

• Jun Liu - Creating a Drug Library to Find Other Uses for FDA Approved Drugs

• Jun Liu - The Job of the Enzyme Methionine Aminopeptidase

• Jun Liu - The Common Thread in All His Research 3/10/10

Recent News Articles and Media Coverage

• Q&A with Jun Liu on teaching an old dog new tricks -- using known drugs to treat new diseases, Hopkins Medicine 

  Immune system 'brakes' found, BBC NEWS  (January 28, 2007)

  With Aid of Drug Library, New Remedies From Old, The New York Times, (April 27, 2009)

  Antibiotic Slows Growth of Bladder, Breast Cancer Cells, Hopkins Medicine (January 19, 2011)

  Solving A Traditional Chinese Medicine Mystery, Hopkins Medicine (March 2, 2011)

  HIV And Breast Cancer May Share A Common Enemy: Nelfinavir, Hopkins Medicine (October 10, 2012)

  Scientists Look For New Drugs In Skin Of Russian Frog, NPR, (December 17, 2012)

  Sugar Transforms a Traditional Chinese Medicine into a Cruise Missile, Hopkins Medicine (September 7, 2016)

  Rapafusyn Developing Compound That May Thwart Common Surgery Complication. JHU Ventures (March 5, 2019)

Additional Academic Titles

Professor of Oncology

Contact for Research Inquiries

Hunterian Building
725 N. Wolfe Street
Baltimore, MD 21205

Phone: (410) 955-4619
Fax: (410) 955-4520

Research Interests

Chemical biology, Molecular and cellular biology, Translational medicine

Lab Website

Jun O. Liu Laboratory - Lab Website

• Exploration of the existing drug space for novel pharmacological activities with translational potential.

  Drug discovery and development is a time-consuming and costly process. To accelerate the process, we have assembled a library of existing drugs, known as the Johns Hopkins Drug Library (JHDL). We have screened the JHDL in both target- and cell-based assays for novel pharmacological activities. To date, we and our collaborators have identified a number of known drugs that exhibited previously unknown activity. The most interesting hits discovered in our lab alone include: (1) Itraconazole, a widely used antifungal drug, was found to possess potent anti-angiogenic activity. Mechanistic deconvolution has revealed that itraconazole operates through a novel mechanism; it blocks endothelial cell cycle progression through the G1 phase of cell cycle via inhibition of mTOR and it also blocks cholesterol trafficking through the lysosome. We and others demonstrated that itraconazole inhibited angiogenesis and tumor xenografts in animal models, which paved the way for itraconazole to enter multiple Phase 2 human clinical studies. To date, itraconazole has shown efficacy in treating non-small cell lung cancer in combination with pemetrexed, metastatic and castration-resistant prostate cancer and basal cell carcinoma. (2) Nitroxoline, a urinary tract antibiotic, was found to inhibit angiogenesis through dual inhibition of the type 2 methionine aminopeptidase and SIRT1 and 2, which culminate in differentiation of endothelial cells. As nitroxoline has a unique distribution with the highest concentration found in the urinary tract, it has potential in the treatment of cancers of the urinary tract including bladder cancer. (3) Nelfinavir, an HIV protease inhibitor, was found to selectively inhibit HER2+ breast cancer cells. Follow-up studies revealed that nelfinavir is a novel type of HSP90 inhibitor, interacting with HSP90 at a site distinct from the binding sites of previously known HSP90 inhibitors. Nelfinavir and improved analogs have potential as new treatment of HER2+ breast cancer. (4) Clofazimine, an important component of the multidrug regimen for treating leprosy since the 1960s, was found to be a novel inhibitor of Kv1.3 channel, thereby blocking the activation of effector memory T cells implicated in a multitude of autoimmune diseases. In addition to the aforementioned hits, novel inhibitors of HIF-1, the hedgehog signaling pathway and the Hippo signaling pathway have also been identified from JHDL by our collaborators.

  Learning From Nature-Natural products as probes of eukaryotic transcription and translation processes.

  Natural products are an invaluable source of both molecular probes and drug leads, particularly anticancer and anti-infective drugs. Triptolide is a natural product isolated from the Thunder God Vine, whose extracts have been used in traditional Chinese medicine as immunosuppressive and anti-inflammatory remedies for centuries. It displays strong inhibition of all cancer cell lines tested to date, with a mean IC50 value in the low nanomolar range. Its molecular mechanism of action, however, remained elusive for decades. Using a top-down approach, we identified XPB, a subunit of the general transcription factor TFIIH, as a molecular target of triptolide. We are currently attempting to gain deeper understanding of the interaction between triptolide and XPB and the cascade of cellular effects as a consequence of binding of triptolide to XPB. We are also making novel analogs of triptolide to improve its pharmacological activity as leads for developing anticancer drugs. In addition to triptolide, we have also been working on a number of natural products, including pateamine A, lactamidomycin and mycalamide that inhibit eukaryotic translation and cancer cell growth.

  Imitating Nature-Generation of natural product-inspired macrocyclic combinatorial libraries for the discovery of novel inhibitors of protein-protein interactions.

  The macrocyclic natural products FK506 and rapamycin are approved immunosuppressive drugs with important biological activities. Both have been shown to inhibit T cell activation, albeit with distinct mechanisms. In addition, rapamycin has been shown to have strong anti-proliferative activity. FK506 and rapamycin share an extraordinary mode of action; they act by recruiting an abundant and ubiquitously expressed cellular protein, the prolyl cis-trans isomerase FKBP, and the binary complexes subsequently bind to and allosterically inhibit their target proteins calcineurin and mTOR, respectively. Structurally, FK506 and rapamycin share a similar FKBP-binding domain but differ in their effector domains. In FK506 and rapamycin, Nature has taught us that switching the effector domain of FK506 to that in rapamycin, it is possible to change the targets from calcienurin to mTOR. We asked the question of whether we can replace the effector domain of rapamycin with yet another structural scaffold to target other proteins in the human proteome. Thus, we designed and generated a library of new macrocycles containing the FKBP-binding domain of rapamycin, which are named rapafucins. It is hoped that the newly generated rapafucins will be able to target novel proteins in the human proteome, particularly protein-protein interactions.

Research Summary

Dr. Liu's primary research interest lies at the interface between chemistry, biology and medicine. He and his research team employ high-throughput screening to identify modulators of various cellular processes and pathways that have been implicated in human diseases, from cancer to autoimmune diseases. Once biologically active inhibitors are identified, they will serve both as probes of the biological processes of interest and as leads for the development of new drugs for treating human diseases.

Among the biological processes of interest are cancer cell growth and apoptosis, angiogenesis, calcium-dependent signaling pathways, eukaryotic transcription and translation.

Current projects include the exploration of the existing drug space for novel pharmacological activities with translational potential; learning from nature—using natural products as probes of eukaryotic transcription and translation processes; and imitating nature—generating natural product-inspired macrocyclic combinatorial libraries for the discovery of novel inhibitors of protein-protein interactions.

PubMed

https://www.ncbi.nlm.nih.gov/myncbi/1H1mbtuSn8qkn/bibliography/public/

Selected Publications

• Guo Z, Cheng Z, Wang J, Liu W, Peng H, Wang Y, Rao AVS, Li RJ, Ying X, Korangath P, Liberti MV, Li Y, Xie Y, Hong SY, Schiene-Fischer C, Fischer G, Locasale JW, Sukumar S, Zhu H, Liu JO. “Discovery of a Potent GLUT Inhibitor from a Library of Rapafucins by Using 3D Microarrays.” Angew Chem Int Ed Engl. 2019 Nov 25; 58:17158-17162. doi: 10.1002/anie.201905578. Epub 2019 Oct 31

• Guo Z, Hong SY, Wang J, Rehan S, Liu W, Peng H, Das M, Li W, Bhat S, Peiffer B, Ullman BR, Tse CM, Tarmakova Z, Schiene-Fischer C, Fischer G, Coe I, Paavilainen VO, Sun Z, Liu JO. “Rapamycin-inspired macrocycles with new target specificity.” Nat Chem. 2019 Mar; 11:254-263. doi: 10.1038/s41557-018-0187-4. Epub 2018 Dec 10

• Li RJ, Xu J, Fu C, Zhang J, Zheng YG, Jia H, Liu JO. “Regulation of mTORC1 by lysosomal calcium and calmodulin.” Elife. 2016 Oct 27; 5:e19360. doi: 10.7554/eLife.19360

• Park H, Kam TI, Peng H, Chou SC, Mehrabani-Tabari AA, Song JJ, Yin X, Karuppagounder SS, Umanah GK, Rao AVS, Choi Y, Aggarwal A, Chang S, Kim H, Byun J, Liu JO, Dawson TM, Dawson VL. “PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease.” Cell 2022 May 26; 185:1943-1959. doi: 10.1016/j.cell.2022.04.020. Epub 2022 May 10

• Peiffer BJ, Qi L, Ahmadi AR, Wang Y, Guo Z, Peng H, Sun Z, Liu JO. “Activation of BMP Signaling by FKBP12 Ligands Synergizes with Inhibition of CXCR4 to Accelerate Wound Healing.” Cell Chem Biol. 2019 May 16; 26:652-661.e4. doi: 10.1016/j.chembiol.2019.01.011. Epub 2019 Feb 28

Honors

• Fellow, American Academy of Microbiology, 1/1/11
• Director's Pioneer Award, National Institutes of Health, 1/1/10
• Fellow, American Association for the Advancement of Science, 1/1/08
• Foundation Award, Prostate Cancer, 1/1/07
• Foundation Scholar, Peter J. Sharp, 1/1/06

Graduate Program Affiliations

• Pharmacology and Molecular Sciences

  Biochemistry, Cellular and Molecular Biology

  Chemistry-Biology Interface (CBI) Program

Professional Activities

Johns Hopkins Malaria Research Institute, Steering Committee

Additional Training

Harvard University, Cambridge, MA, 1990, Biochemistry