Drug Discovery, Chemical Biology, and Medicinal Chemistry; Organic
Cancer is a complex and multifactorial problem that we often seek to treat with one-dimensional solutions, not surprisingly with limited practical gain in overall patient survival. Work in my lab aims to harness the power of organic synthesis to develop materials and approaches that address the problem underlying current uni-targeted approaches - the rapid resistance emergence, the evasive cancer stem cells, and the brief period of positive clinical outcome for cancer patients. It is anticipated that vigorous efforts in this direction will illuminate many areas of chemical and life sciences, and may result in innovative platforms to target future therapies. Our approach is interdisciplinary, combining ligand design and synthesis, combinatorial chemistry and high-throughput screening with bioinformatics, structural, molecular and cell biology, with the ultimate goal of revealing new basic biological mechanisms and disease treatments.
Specific projects in the group include:
Chemical Synthetic Lethality: Development of Multifunctional Ligands for Targeting Triple Negative Breast Cancer. We take advantage of 'synthetic lethal' interactions in a cancer cell (for e.g., mutations in BRCA1 protein), and develop agents that have increased potency and activity only in the presence of specific genetic alterations, thus making them selective for cancer cells but non-toxic for normal cells.
Drugging the Undruggable: Stapled Peptides and Small Molecule Approaches to Target Protein-Protein Interactions. We are developing in silico design strategies, coupled with biophysical and biochemical assays to discover small molecules and stabilized (stapled) peptides that target the hitherto undruggable protein-protein interaction domains. Our focus is particularly in targeting Estrogen Receptor signaling to define the role of these domains in genomic and non-genomic activity in cells, expand the repertoire of targets for drug discovery, and potentially impact the resistant forms of Breast Cancer in novel ways.
Precision Medicine: Development of Phenotype-Selective Multivalent Anti-Tumor Agents. Our group develops multivalent ligands that are lethal to tumor cells of a specific phenotype. These ligands act as guided missiles for delivering drugs or imaging moieties to desired tissues for theranostic purposes. Alternatively, we also explore various liposome and polymer based nanoparticles for delivery of drugs and imaging agents. We are seeking to develop this technology for targeting stem cell population and tumor-associated (hijacked) macrophages (TAMs).
Doodle-Dabbles. Along the way, we like to tinker with small side-projects to see where they go and if we could develop pioneering methods to advance the drug discovery process.
- Josan J.S., and Katzenellenbogen, J.A. Designer antiandrogens join the race against drug resistance. eLife, 2013, 2, e00692.
- Xu L., Josan J.S., Vagner J., Caplan M.R., Hruby V.J., Mash E.A., Lynch R.M., Morse D.L., and Gillies R.J. Heterobivalent ligands target cell-surface receptor combinations in vivo. Proc. Natl. Acad. Sci. USA, 2012, 109, 21295-21300.
- Josan J.S., Handl H.L., Sankaranarayanan R., Xu L., Lynch R.M., Vagner J., Mash E.A., Hruby V.J., and Gillies R.J. Cell-specific targeting by heterobivalent ligands. Bioconjugate Chem., 2011, 22, 1270-1278.(Featured on Journal Cover - July 20, 2011)
- Barkey N.M., Tafreshi N.K., Josan J.S., DeSilva C.R., Sill K.N., Hruby V.J., Gillies R.J., Morse D.L., and Vagner J. Development of melanoma-targeted polymer micelles by conjugation of a melanocortin 1 receptor (MC1R) specific ligand. J. Med. Chem., 2011, 54, 8078-8084. (Highlighted in ScienceDaily - Nov 4, 2011)
- Josan J.S., DeSilva C.R., Yoo B., Lynch R.M., Pagel M.D., Vagner J., and Hruby V.J. Fluorescent and lanthanide labeling for ligand screens, assays, and imaging. In Drug Design & Discovery: Methods & Protocols(Methods in Molecular Biology), Humana Press NY, 2010, 716: 89-126.
- Josan J.S., Morse D.L., Xu L., Trissal M., Baggett B., Davis P., Vagner J., Gillies R.J., and Hruby V.J. Solid-phase synthetic strategy and bioevaluation of a labeled delta-opioid receptor ligand Dmt-Tic-Lys for in vivo imaging. Org. Lett., 2009, 11, 2479-2482.
- Xu L., Vagner J., Josan J.S., Lynch R.M., Morse D.L., Baggett B., Han H., Mash E.A., Hruby V.J., and Gillies R.J. Enhanced targeting with heterobivalent ligands. Mol. Cancer Ther., 2009, 8, 2356-2365.
- Vagner J., Xu L., Handl H.L., Josan J.S., Morse D.L., Mash E.A., Gillies R.J., Hruby V.J. Heterobivalent ligands cross-link multiple cell-surface receptors: the human melanocortin-4 receptor and the delta-opioid receptor. Angew. Chem. Int. Ed., 2008, 47, 1685-1688.
- Josan J.S., Vagner J., Handl H.L., Sankaranarayanan R., Gillies R.J., and Hruby V.J. Solid-phase synthesis of heterobivalent ligands targeted to melanocortin and cholecystokinin receptors. Int. J. Pep. Res. & Ther., 2008, 14, 293-300.
- Handl H., Sankaranarayanan R., Josan J.S., Vagner J., Xu L., Morse D.L., Gillies R.J., Hruby V.J. Synthesis and evaluation of bivalent NDP-a-MSH(7)H(7) peptide ligands for binding to the human melanocortin receptor 4 (hMC4R). Bioconugate Chem., 2007, 18, 1101-1109.
- Department of Defence CDMRP Postdoctoral Fellowship, 2012
- American Peptide Society (APS) Young Investigator Award, 2009
- Contrast Media Research (CMR) Young Investigator Award, 2007
- Technology Research Initiative Fund (TRIF) Imaging Fellowship, 2007–2008
- Victor J. Hruby Fellowship in Peptide Research, 2007
- UA Department of Chemistry Mid-Career Fellowship, 2004–2006
- B. Pharmacy, GND University, India, 2000
- M.S. Medicinal Chemistry, NIPER, India, 2001
- Research Associate, Ranbaxy Labs Ltd. (Now Daiichi Sankyo), 2002
- JRF, National Institute of Immunology, 2003
- Ph.D. University of Arizona, 2008
- Postdoctoral Associate, University of Illinois, 2010–2013