Medicinal Chemistry, Biotechnology, Chemosessors, Cancer Biology, Rare Disease Therapeutics
Most biological processes involve permanent and nonpermanent interactions between different proteins. Many protein complexation events play key roles in various human diseases. The thrust of our research focuses on the development of novel, small molecule architectures to reverse a protein's aberrant role, via manipulation of protein complexation events. Numerous protein-protein interfaces contain compact, centralized regions of residues, known as 'hot spots', crucial for interaction. Many proteins function by binding to multiple partners and these proteins tend to use the same hot spots, which can adapt to present the same residues in different structural contexts.
Our research seeks to design and develop scaffolds to artificially suppress or up-regulate specific gene expression profiles via manipulation of protein-protein interactions, thereby inducing therapeutically-beneficial cellular responses in malfunctioning human cells. The proposed research seeks to validate whether protein function can be 'switched' on or off through artificial protein complexation by divalent conjugated small molecule 'hot spot' recognition agents. Molecular modulation of specific protein-protein interactions offers a dynamic approach to artificially regulating aberrant protein activity in human disease. A keen objective of the proposed work is to promote and illuminate the efficacy of developing novel drug-like scaffolds incorporating inorganic, as well as organic, functionality to achieve in vivo manipulation of cellular signaling.
CHM243H5, CHM345H5, CHM444H5 (undergraduate) and CHM1009H (graduate)
Rationally Designed STAT3 Protein Inhibitors as Pancreatic Cancer Therapeutics. Arpin, C. C., Mac, S., Cheng, H., Jiang, Y., Page, B. D. G., Kamocka, M. M., Haftchenary, S., Su, H., Ball, D., Rosa, D., Lai, P-S., Gómez-Biagi, R. F., Ali, A. M., Kerman, K., Fishel, M. L., and Gunning, P. T. Mol. Cancer Ther. 2015 accepted, in press. MS# MCT-15-0003
A tool for the selective sequestration of ATP and PPi to aid in-solution phosphopeptide detection assays.Duodu, E., Kraskouskaya, D., Gunning, P. T. Analyst. 2015, in press. AN-COM-07-2015-001414.
A selective inhibitor of the UFM1-activating enzyme, UBA5. da Silva, S. R., Paiva, S-L., Bancerz, M., Geletu, M., Lewis, A. M., Chen, J., Cai, Y., Lukkarila, J. L., Dhe-Paganon, S., Li, H., Gunning, P. T. BMCL. 2015 in press. Manuscript # MCL_BMCL-D-15-00846. DOI:10.1016/j.bmcl. 2015.10.015
Targeting Signal Transducer and Activator of Transcripion (STAT) 3 with Small Molecules. Shouksmith, A. E., Gunning, P. T. Book chapter for Royal Society of Chemistry Book, ‘Small Molecule Transcription Factors in Oncology.’ 2015.
A STAT inhibitor patent review: progress since 2011. Lai, P.L., Rosa, D. A., Ali, A. M., Gomez-Biagi, R. E., Ball, D. P., Shouksmith, A. E., Gunning, P. T. Ex. Opin. Ther. Pat. 2015, in press. Manuscript ID: 1086749.
Identification of Bidentate Salicylic Acid Inhibitors of PTP1B. Haftchenary, S, Jouk, A. O., Aubry, I., Lewis, A. M., Landry, M., Ball, D. P., Shouksmith, A. E., Collins, C. V., Tremblay, M. L., Gunning, P. T. ACS Med. Chem. Lett. 2015, 6, 982–986.
STAT3 pathway regulates lung-derived brain metastasis initiating cell capacity through miR-21 activation. Singh, M., Garg, N., Venugopal, C., Hallett, R., Tokar, T., McFarlane, N., Arpin, C. C., Page, B. D. G., Haftchenary, S., Todic, A., Rosa, D. A., Lai, P-S., Gómez-Biagi, R., Ali, M., Lewis, A., Geletu, M., Mahendram, S., Bakhshinyan, D., Manoranjan, B., Vora, P., Qazi, M., Murty, N. K., Hassell, J. A., Jurisica, I., Gunning, P. T., Singh, S. K. Oncotarget. 2015, 6, 27461-27477.
Signal transducer and activator of transcription 3 and 5 regulate system Xc- and redox balance in human breast cancer cells. Linher-Melville, K., Haftchenary, S., Gunning, P. T., Singh, G. Mol. Cell. Biochem. 2015, 405, 205-221.