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: firstname.lastname@example.org
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 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.
- 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 drugsthat 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. 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. We asked the question of whether we can replace the effector domain of rapamycin with yet another structural scaffold to confer novel protein target specificity. 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.
- Kishor, C., Arya, T., Teddi, R., Chen, X., Saddanapu, V., Marapaka, A.K., Gumpena, R., Ma, D., Liu, J.O., Addlagatta, A. Identification, biochemical and structural evaluation of species-specific inhibitors against type I methionine aminopeptidases. J. Med. Chem. 56:5295-5305, 2013.
- Liu, C., Ma, H., Wu, J., Huang, Q., Liu, J.O., Yu, L. Arginine68 is an essential residue for the C-terminal cleavage of human Atg8 family proteins. BMC Cell Biol. 14:27, 2013.
- Kong, X., Peng, B., Yang, Y., Zhang, P., Qin, B., Han, D., Wang, C., Dang, Y., Liu, J.O., Yu, L. p53 represses transcription of RING finger LIM domain-binding protein RLIM through Sp1. PLoS One 8, e62832, 2013.
- Zhang, F., Bhat, S., Gabelli, S.B., Chen, X., Miller, M.S., Nacev, B.A., Cheng, Y.L., Meyers, D.J., Tenney, K., Shim, J.S., Crews, P., Amzel, L.M., Ma, D., Liu, J.O. Pyridinylquinazolines selectively inhibit h uman methionine aminopeptidase-1 in cells. J. Med. Chem. 56:3996-4016, 2013.
- Fatokun, A.A., Liu, J.O., Dawson, V.L., Dawson, T.M. Identification through high-throughput screening of 4;-methoxyflavone and 3',4'-dimethoxyflavone as novel neuroprotective inhibitors of parthanatos. Br. J. Pharmacol. 169:1263-1278, 2013.
- Rudin, C.M., Brahmer, J.R., Juergens, R.A., Hann, C.L., Ettinger, D.S., Sebree, R., Smith, R., Aftab, B.T., Huang, P., Liu, J.O. Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer. J. Thorac. Oncol. 8:619-623, 2013.
- Bhat, S., Shim, J.S., Liu, J.O. Tricyclic thiazoles are a new class of angiogenesis inhibitors. Bioorg. Med. Chem. Lett. 23:2733-2737, 2013.
- Zhang, P., Yang, X., Zhang, F., Gabelli, S.B., Wang, R., Zhang, Y ., Bhat, S., Chen, X., Furlani, M., Amzel, L.M., Liu, J.O., Ma, D. Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1. Bioorg. Med. Chem. 21:2600-2617, 2013.
- Wissing, M.D., Mendonca, J., Kim, E., Shim, J.S., Kaelber, N.S., Kant, H., Hammers, H., Commes, T., Van Diest, P.J., Liu, J.O., Kachhap, S.K. Identification of cetrimonium bromide and irinotecan as compounds with synthetic lethality against NDRG1 deficient prostate cancer cells. Cancer Biol. Ther. 14:401-410, 2013.
- Choi, S.M., Kim, Y., Shim, J.S., Park, J.T., Wang, R.H., Leach, S.D., Liu, J.O., Deng, C.X., Ye, Z., Jang, Y.Y. Efficient drug screening and gene correction for treating liver disease using patient-specific stem cells. Hepatology 57:2458-2468, 2013.
- Kamiyama, H., Rauenzahn, S., Shim, J.S., Karikari, C.A., Feldmann, G., Hua, L., Kamiyama, M., Schuler, F.W., Lin, M.T., Beaty, R.M., Karanam, B., Liang, H., Mullendore, M.E., Mo, G., Hidalgo, M., Jaffee, E., Hruban, R.H., Jinnah, H.A., Roden, R.B., Jimeno, A., Liu, J.O., Maitra, A., Eshleman, J.R. Personalized chemotherapy profiling using cancer cell lines from selectable mice. Clin. Cancer Res. 19:1139-1146, 2013.
- Kurata, S., Shen, B., Liu, J.O., Takeuchi, N., Kaji, A., Kaji, H. Possible steps of complete disassembly of post-termination complex by yeast eEF3 deduced from inhibition by translocation inhibitors. Nucleic Acids Res. 41:264-276, 2013.
- Yang, Y., Wang, C., Zhang, P., Gao, K., Wang, D., Yu, H., Zhang, T., Jiang, S., Hexige, S., Hong, Z., Yasui, A., Liu, J.O., Huang, H., Yu, L. Polycomb group protein PHF1 regulates p53-dependent cell growth arrest and apoptosis. J. Biol. Chem. 288:529-539, 2013.
- Shim, J.S., Rao, R., Beebe, K., Neckers, L., Han, I., Nahta, R., Liu, J.O. Selective inhibition of Her2-positive breast cancer cells by the HIV protease inhibitor nelfinavir. J. Natl. Cancer Inst. 104:1576-1590, 2012.
- Chen, X.Y., Gu, X.T., Saiyin, H., Wan, B., Zhang, Y.J. Li, J. Wang, Y.L, Gao, R., Wang, Y.F., Dong, W.P., Najjar, S.M., Zhang, C.Y., Ding, H.F., Liu, J.O., Yu, L. Brain-selective kinase 2 (BRSK2) phosphorylation on PCTAIRE1 negatively regulates glucose-stimulated insulin in pancreatic ß-cells. J. Biol. Chem. 287:30368-30375, 2012.
- Krátký, M., Vinšová, J., Novotná, E., Mandiková, J., Wsól, V., Trejtnar, F., Ulmann, V., Stolařiková, J, Fernandes, S., Bhat, S., Liu, J.O. Salicylanilide derivatives block Mycobacterium tuberculosis through inhibition of isocitrate lyase and methionine aminopeptidase. Tuberculosis 92:434-439, 2012.
- Liu-Chittenden, Y., Huang, B., Shim, J.S., Chen, Q., Lee, S.J., Anders, R.A., Liu, J.O., Pan, D. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 26:1300-1305, 2012.
- Bhat, S., Olaleye, O., Meyer, K.J., Shi, W., Zhang, Y., Liu, J.O. Analogs of N'-hydroxy-N-(4H, 5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide inhibit Mycobacterium tuberculosis methionin aminopeptidases. Bioorg. Med. Chem. 20:4507-4513, 2012.
- Bhat, S., Shim, J.S., Zhang, F., Chong, C.R., Liu, J.O. Substituted oxines inhibit endothelial cell proliferation and angiogenesis. Org. Biomol. Chem. 10:2979-2992. 2012.
- Wang, C., An, J., Zhang, P., Xu, C., Gao, K., Wu, D., Wang, D., Yu, H., Liu, J.O., Yu, L. The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation. Biochem. J. 444:279-289, 2012.
- Titov, D.V., Liu, J.O. Identification and validation of protein targets of bioactive small molecules. Bioorg. Med. Chem. 20:1902-1909, 2012.
- Xing, S., Bhat, S., Shroff, N.S., Zhang, H., Lopez, J.A., Margolick, J.B., Liu, J.O., Siliciano, R.F. Novel structurally related compounds reactivate latent HIV-1 in a bcl-2-transduced primary CD4+T cell model withough inducing global T cell activation. J. Antimicrob. Chemother. 67, 398-403, 2012.
- Olaleye, O., Raghunand, T.R., Bhat, S., Chong, C., Gu, P., Zhou, J., Zhang, Y., Bishai, W.R., Liu, J.O. Characterization of clioquinol and analogues as novel inhibitors of methionine aminopeptidases from Mycobacterium tuberculosis. Tuberculosis Suppl 1, S61-65, 2011.
- Peng, C.C., Shi, W., Lutz, J.D., Kunze, K.L., Liu, J.O., Nelson, W.L., Isoherranen, N. Stereospecific metabolism of itraconazole by CYP3A4: dioxolane ring scission of azole antifungals. Drug Metab. Dispos. 40: 426-435, 2011.
- Rovira, M., Huang, W., Yusuff, S., Shim, J.S., Ferrante, A.A., Liu, J.O., Parsons, M.J. Chemical screen identifies FDA-approved drugs and target pathways that induce precocious pancreatic endocrine differentiation. Proc. Natl. Acad. Sci. USA 108:19264-19269, 2011.
- Nacev, B.A., Grassi, P., Dell, A., Haslan, S.M., Liu, J.O. The antifungal drug itraconazole inhibits vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, trafficking and signaling in endothelial cells. J. Biol. Chem. 286:44045-44056, 2011.
- Chamni, S., He, Q.L., Dang, Y., Bhat, S., Liu, J.O., Romo, D. Diazo reagents with small steric footprints for simultaneous arming/SAR studies of alcohol-containing natrual products via O-H insertion. ACS Chem. Biol. 6:1175-1181, 2011.
- Aftab, B.T., Dobromilskaya, I., Liu, J.O., Rudin, C.M. Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer. Cancer Res. 71:6764-6772, 2011.
- Nacev, B.A., Liu, J.O. Synergistic inhibition of endothelial cell proliferation, tube formation, and sprouting by cyclosporine A and itraconazole. PLoS One 6, e24793, 2011.
- Shi, W., Nacev, B.A., Aftab, B.T., Rudin, C.M., Liu, J.O. Itraconazole side chain analogues: Structure-activity relationship studies for inhibition of endothelial cell proliferation, vascular endothelial growth factor receptor 2 (VEGF2) glycosylation, and hedgehog signaling. Med. Chem. 54:7363-37374, 2011.
- Li, W., Bhat, S., Liu, J.O. A simple and efficient route to the FKBP-binding domain from rapamycin. Tetrahedron Lett. 52:5070-5072, 2011.
Dang, Y., Schneider-Poetsch, T., Eyler, D.E., Jewett, J.C., Bhat, S., Rawal, V.H., Green, R., Liu, J.O. Inhibition of eukaryotic translation elongation byt the antitumor natural product Mycalamide B. RNA 17:1578-1588, 2011.
Nacev, B., Low, W.K., Huang, Z., Su, T., Su, Z., Alkuraya, H., Kasuga, D., Sun, W., Tranger, M., Braun, M., Fischer, G., Zhang, K., Liu, J.O. A calcineurin-independent mechanism of angiogenesis inhibition by a non-immunosupporessive cyclosporin A analog. J. Pharmacol. Exp. Ther. 338:466-475, 2011.
- Platz, E.A., Yegnasubramanian, S., Liu, J.O., Chong, C.R., Shim, J.S., Kenfield, S.A., Stampfer, M.J., Willett, W.C., Giovannucci, E., Nelson, W.G. A novel two-stage, transdisciplinary study identifies digoxin as a possible drug for prastate cancer treatment. Cancer Discovery 1:68-77, 2011.
- Wilson, B.A., Wang, H., Nacev, B.A., Mease, R.C., Liu, J.O., Pomper, M.G., Isaacs, W.B. High-throughput screen identifies novel inhibitiors of cancer biomarker amethyacyl coenzyme A rasemase (AMACR/P504S). Mol. Cancer Ther. 10:825-838, 2011.
- Titov, D.V., Gilman, B., He, Q., 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.
- He, J., Ye, J., Cai, Y., Riquelme, C., Liu, J.O., Liu, X., Han, A., Chen, L. Structure of p300 bound to MEF2 on DNA reveals a mechanism of enhanceosome assembly. Nucleic Acids Res. 39:4464-4474, 2011.
- Liu, J.O., Titov, D.V., Dang, Y., He, Q. Regulator of ras depalmitoylation and retrograde trafficking: a new hat for FKBP. Mol. Cell 41:131-133, 2011.
- Shim, J.S., Matsui, Y., Bhat, S., Nacev, B.A., Xu, H., 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 Instl. 102:1855-1873, 2010.
- Lin, J., Haffner, M.C., Zhang, Y., Lee, B.H., Brennen, W.N., Britton, J., Kachhap, S.K., Shim, J.S., Liu, J.O., Nelson, W.G., Yegnasubramanian, S., Carducci, M.A. Disulfiram is a DNA demethylating agent and inhibits prostate cancer cell growth. Prostate 71:333-343, 2010.
- Zhu, P., Jiang, W., Cao., L., Yu, W., Pei, Y., Yang, X., Wan, B., Liu, J.O., Yi, Q., Yu, L. IL-2 mRNA stabilization upon PMA stimulation is dependent on NF90-Ser647 phosphorylation by protein kinase CbI. J. Immunol. 185:5140-5149, 2010.
- Huang, W., Ding, L., Huang, Q., Hu, H., Liu, S., Yang, X., Hu, X., Dang, Y., Shen, S., Li, J., Ji, X., Jiang, S., Liu, J.O., Yu, L. Carbonyl reductase 1 as a novel target of (-)-epigallocatechin gallate against hepatocellular carcinoma. Hepatology 52:703-714, 2010.
- Xiao, Q., Zhang, F., Nacev, B.A., Liu, J.O., and Pei, D. Protein N-terminal processing: substrate specificity of Escherichia coli and human methionine aminopeptidases. Biochemistry 49:5588-5599, 2010.
- Shi, W., Nacev, B.A., Bhat, S., Liu, J.O. Impact of absolute stereochemistry on the antiangiogenic and antifungal activities of itraconazole. ACS Med. Chem. Lett. 1:155-159, 2010.
- Li, W., Dang, Y., Liu, J.O., and Yu, B. Structural and stereochemical requirements of the spiroketal group of hippuristanol for antiproliferative activity. Bioorg. Med. Chem. Lett. 20:3112-3115, 2010.
- Kim, J., Tang, J.Y., Gong, R., Kim, J., Lee, J.J., Clemons, K.V., Chong, C.R., Chang, K.S., Fereshte, 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.
- 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 107:4764-4769. 2010.
- 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.
- Olaleye, O.A., Taghunand, R.R., Bhat, S., He, J., Tyagi, S., Lamichhane, G., Gu, P., Zhou, J., Zhang, Y., Grosset, J., Bishai, W.R., Liu, J.O. Methionin aminopeptidases from Mycobacterium tuberculosis as novel antimycobacterial targets. Chem. Biol. 17:86-97, 2010.
- Zhang, P., Wang, C., Gao, K., Wang, D., Mao, J., An, J., Xu, C., Wu, D., Yu, H., Liu, J.O., Yu, L. The ubiquitin ligase itch regulates apoptosis by targeting thioredocin-interacting protein for ubiquitin-dependent degradation. J. Biol. Chem. 285:8869-8879, 2010.
- Yang, H.C., Xing, S., Shan, L., O'Connell, K., Dinoso, J., Shen, A., Zhou, Y., Shrum, C.K., Han, Y., Liu, J.O., Zhang, H., Margolick, J.B., Siliciano, R.F. Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation. J. Clinic. Invest. 119:3473-3489, 2009.
- Lee, K., Zhang, H., Qian, D.Z., Rey, S., Liu, J.O., Semenza, G.L. Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proc. Natl. Acad. Sci. USA 106:17910-17915, 2009.
- Li, W., Dang, Y., Liu, J.O., Yu, B. Expeditious Synthesis of Hippuristanol and Congeners with Potent Antiproliferative Activities. Chemistry, Eur. J. 15:10356-10359, 2009.
- Pan, F., Yu, H., Dang, E.V., Barbi, J., Pan, X., Grosso, J.F., Jinasena, D., Sharma, S.M., McCadden, E.M., Getnet, D., Drake, C.G., Liu, J.O., Ostrowski, M.C., Pardoll, D.M. Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science 325:1142-1146, 2009.
- Woodard, L.E., Chang, W., Chen, X., Liu, J.O., Shapiro, T.A., Posner, G.H. Malaria-Infected Mice Live until at Least Day 30 after a New Monomeric Trioxane Combined with Mefloquine Are Administered Together in a Single Low Oral Dose. J. Med. Chem. 52:7458-7462, 2009.
- Dang, Y., Low, W.K., Xu, J., Gehring. N. H., Dietz, H.C., Romo, D., Liu, J.O. Inhibition of nonsense-mediated mRNA decay by the natural product pateamine A through eukaryotic initiation factor 4AIII. J. Biol. Chem. 284: 23613-23621, 2009.
- Zhang, Y., Byun, Y., Ren, Y.R., Liu, J. O., Laterra, J., Pomper, M.G. Identification of inhibitors of ABCG2 by a bioluminescence imaging-based high-throughput assay. Cancer Res. 69:5867-5875, 2009.
- Liu, J.O., Nacev, B.A., Xu, J., Bhat, S. It takes two binding sites for calcineurin and NFAT to tango. Mol. Cell 33: 676-678, 2009.
- Rosenthal, A.S., Chen, X., Liu, J.O., West, D.C., Hergenrother, P.J., Shapiro, T.A., Posner, G.H. Malaria-Infected Mice Are Cured by a Single Oral Dose of New Dimeric Trioxane Sulfones Which Are Also Selectively and Powerfully Cytotoxic to Cancer Cells. J. Med. Chem 52:1198-1203, 2009.
- Liu, J.O. Calmodulin-dependent phosphatase, kinases, and transcriptional corepressors involved in T-cell activation. Immunol. Rev. 228:184-198, 2009.
- Chen, X., Xie, S., Bhat, S., Kumar, N., Shapiro, T.A., Liu, J.O. Fumagillin and fumarranol interact with P. falciparum methionine aminopeptidase 2 and inhibit malaria parasite growth in vitro and in vivo. Chem. Biol. 16:193-202, 2009.
- Lee, K., Qian, D.Z., Rey, S., Wei, H., Liu, J.O., Semenza, G.L. Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc. Natl. Acad. Sci. USA 106:2353-2358, 2009.
Other graduate programs in which Dr. Liu participates: