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School of Medicine
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Jun O. Liu
Department Affiliation: Primary: Pharmacology and Molecular Sciences; Secondary: Oncology
Degree: Ph.D., Massachusetts Institute of Technology
Telephone Number: 410-955-4619
Fax Number: 410-955-4520
E-mail address: email@example.com
School of Medicine Address: Room 516 Hunterian Building, 725 N. Wolfe Street, Baltimore, MD 21205
Chemical biology, molecular and cellular biology, and translational medicine
Our primary research interest lies at the interface between chemistry, biology and medicine. We 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 compounds are identified, they will serve as both probes of the biological processes of interest and leads for the development of new drugs for treating human diseases.
Among the biological processes of interest are cancer cell growth and mestastasis, apoptosis, angiogenesis, calcium-dependent signaling pathways, eukaryotic transcription and translation. Some of the ongoing projects are highlighted herein.
• 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
Table 1. New Activity of Existing Drugs
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 and anti-hedgehog signaling activity. Mechanistic deconvolution has revealed that itraconazole operates through a novel dual-targeted mechanism of action for its anti-angiogenic activity, by which it blocks endothelial cell cycle progression through the G1 phase of cell cycle via inhibition of mTOR signaling. We have identified and validated two molecular targets for itraconazole, the voltage-dependent anion channel (VDAC)1 and Niemann Pick Disease type C (NPC)1. While inhibition of VDAC leads to a decrease in cellular ATP levels and activation of the AMPK pathway, inhibition of NPC1 causes accumulation of cholesterol in the endolysosome and consequently defects in lysosomal calcium signaling. Together, these effects converge to synergistic inhibition of mTOR. We and others have demonstrated that itraconazole inhibited angiogenesis and tumor xenograft growth 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. Itraconazole, along with its new formulation and one of its stereoisomers are now in different phases of human clinical trials. (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. Upon confirming its effect in a mouse orthotopic bladder cancer model, it has entered into a Phase 3 human trial for treating bladder cancer. (3) Nelfinavir, an HIV protease inhibitor, was found to selectively inhibit HER2+ breast cancer cell. 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 treatments for 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 those with anticancer and anti-infective activities. 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 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 have gained new insight into how triptolide binds to XPB—through covalent modification of an active site cysteine with one of its epoxide groups. On the translational front, various analogs of triptolide have been developed as leads for developing anticancer drugs with very limited success. Two of the limitations for triptolide as a drug lead are its general toxicity and low solubility. To address those problems, we have designed glucose-triptolide conjugates to both increase its solubility and to selectively target triptolide to cancer cells that overexpress glucose transporters (Fig. 1). We have found that a glucose-triptolide conjugate indeed exhibited higher cytotoxicity to cancer cells than normal cells. Moreover, it showed sustained anticancer activity in animal models. Glutriptolide is undergoing preclinical development and has the potential to become a new weapon with greater precision in the war against cancer.
• Imitating Nature--Generation of natural product-inspired macrocyclic combinatorial libraries for the discovery of novel inhibitors of protein-protein interactions and membrane proteins.
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. Both have become approved immunosuppressive and/or anticancer drugs. 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. The presence of the FKBP-binding domains in FK506 and rapamycin confer a number of advantages, including stability, higher intracellular accumulation, larger size and superior in vivo pharmacological activity. We asked the question of whether we can leverage on this highly privileged scaffold offered by nature by replacing the effector domain of rapamycin with yet another structural scaffold to confer novel protein target specificity. Thus
we designed and generated a library of over 45,000 novel macrocycles containing the FKBP-binding domain, which are named rapafucins (Fig. 2). To date, we have identified multiple potent inhibitors of membrane protein targets as well as protein-protein interactions involving transcription factors. To our delight, several of the optimized hits have shown anticancer and immunomodulatory activity in animal models, suggesting that rapafucins are bioavailable and active in vivo. It is hoped that the newly generated rapafucins will be able to target novel proteins in the human proteome, particularly protein-protein interactions. We anticipate that rapafucins will become an important new source of chemical probes and drug leads
Chong, C.R., Chen, X., Shi, L., Liu, J.O., and Sullivan, D.J. A clinical drug library screen identifies astemizole as an antimalarial agent. Nat Chem Biol, 2, 415-416, 2006. Pub Med Reference
Chong, C.R., Xu, J., Lu, J., Bhat, S., Sullivan, D.J., Jr., Liu, J.O. Inhibition of angiogenesis by the antifungal drug itraconazole. ACS Chem Biol, 2, 263-70, 2007. Pub Med Reference
Kim, J., Tang, J.Y., Gong, R., Kim, J., Lee, J.J., Clemons, K.V., Chong, C.R., Chang, K.S., Fereshteh, M., Gardner, D., Reya, T., Liu, J.O., Epstein, E. H., Stevens, D. A., Beachy, P. A. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell, 17, 388-399, 2010. Pub Med Reference
Xu, J., Dang, Y., Ren, Y.R., Liu, J.O. Cholesterol trafficking is required for mTOR activation in endothelial cells. Proc Natl Acad Sci USA, 107, 4764-9, 2010. Pub Med Reference
Shim, J.S., Matsui, Y., Bhat, S., Nacev, B.A., Xu, J., Bhang, H.E., Dhara, S., Han, K.C., Chong, C.R., Pomper, M.G., So, A., Liu, J.O. Effect of nitroxolibne on angiogenesis and growth of human bladder cancer. J Natl Cancer Inst, 102, 1855-1873, 2010. Pub Med Reference
Head, S.A., Shi, W., Zhao, L., Gorshkov, K., Pasunooti, K., Chen, Y., Deng, Z., Li, R.J., Shim, J.S., Tan, W., Hartung, T., Zhang, J., Zhao, Y., Colombini, M., Liu, J.O. Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells. Proc Natl Acad Sci USA, 112, E7276-7285, 2015. Pub Med Reference
Shim, J.S., Li, R.J., Bumpus, N.N., Head, S.A., Kumar Pasunooti, K., Yang, E.J., Lv, J., Shi, W., and Liu, J.O. Divergence of Antiangiogenic Activity and Hepatotoxicity of Different Stereoisomers of Itraconazole. Clin Cancer Res, 22, 2709-2720, 2016. Pub Med Reference
Head, S.A., Shi, W. Q, Yang, E.J., Nacev, B.A., Hong, S.Y., Pasunooti, K.K., Li, R.J., Shim, J.S., and Liu, J.O. Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis. ACS Chem Biol, 12, 174-182, 2017. Pub Med Reference
Chemical biology of natural products
Low, W.-K., Dang, Y., Schneider-Poetsch, T., Shi, Z., Choi, N.S., Merrick, W.C., Romo, D., Liu, J.O. Inhibition of eukaryotic translation initiation by the marine natural product pateamine A. Mol Cell, 20, 709-722, 2005. Pub Med Reference
Schneider-Poetsch, T., Ju, J., Eyler, D.E., Dang, Y., Bhat, S., Merrick, W.C., Green, R., Liu, J.O. Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin. Nat Chem Biol, 6, 209-217, 2010. Pub Med Reference
Titov, D.V., Gilman, B., He, Q.L., Bhat, S., Low, W.K., Dang, Y., Smeaton, M., Demain, A.L., Miller, P.S., Kugel, J.F., Goodrich, J.A., Liu, J.O. XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nat Chem Biol, 7, 182-188. 2011. Pub Med Reference
McClary, B., Zinshteyn, B., Meyer, M., Jouanneau, M., Pellegrino, S., Yusupova, G., Schuller, A., Reyes, J.C.P., Lu, J., Guo, Z., Ayinde, S., Luo, C., Dang, Y., Romo, D., Yusupov, M., Green, R., Liu, J.O. Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A. Cell Chem Biol, 24, 605-613, 2017. Pub Med Reference
He, Q.L., Titov, D.V., Li, J., Tan, M., Ye, Z., Zhao, Y., Romo, D., Liu, J.O. Covalent modification of a cysteine residue in the XPB subunit of the general transcription factor TFIIH through single epoxide cleavage of the transcription inhibitor triptolide. Angew Chem Int Ed, 54, 1859-1863, 2014. Pub Med Reference
He, Q.L., Minn, I., Wang, Q., Xu, P., Head, S.A., Datan, E., Yu, B., Pomper, M.G., Liu, J.O. Targeted Delivery and Sustained Antitumor Activity of Triptolide through Glucose Conjugation. Angew Chem Int Ed, 55, 12035-12039, 2016. Pub Med Reference
Youn, H.-D., Sun, L., Prywes, R., Liu, J.O. Apoptosis of T cells mediated by Ca2+-induced release of the transcription factor MEF2. Science, 286, 790-793, 1999. Pub Med Reference
Han, A., Pan, F., Stroud, J.C., Youn, H.–D., Liu, J.O., Chen, L. Structural basis of sequence-specific recruitment of transcription corepressor Cabin1 by Myocyte Enhancer Factor-2. Nature, 422, 730-734, 2003. Pub Med Reference
Pan, F., Sun, L., Dardian, D.B., Whartenby, K.A., Pardoll, D.M., Liu, J.O. Feedback inhibition of calcineurin and Ras by a dual inhibitory protein Carabin. Nature, 445, 433-436, 2007. Pub Med Reference
Li, R.J., Xu, J., Fu, C., Zhang, J., Zheng, Y.G., Jia, H., Liu, J.O. Regulation of mTORC1 by lysosomal calcium and calmodulin. Elife, 5, e19360, 2016. Pub Med Reference
Li, W., Bhat, S., Liu, J.O. (2011) A simple and efficient route to the FKBP-binding domain from rapamycin. Tetrehedron Lett, 52, 5070-5072, 2011. Pub Med Reference
Guo, Z., Hong, S.Y., Wang, J., Liu, W., Peng, H., Das, M., Li, W., Rehan,S., Bhat, S., Peiffer, B., Tse, C.-M., Tarmakova, Z., Schiene-Fischer, C., Fischer, G., Coe, I., Paavilainen, V.O., Sun, Z., Liu, J.O. Rapafucins, rapamycin-inspired macrocycles with new target specificity. Nat Chem, in revision, 2018.
Other graduate programs in which Dr. Liu participates: