Targeting the Inhibition of Protein-Protein Interactions
My work in the fields of organic methodology, natural product synthesis and medicinal chemistry has directed my own research interests towards questions I intend to investigate with research students attending smaller and engaging institutions. I aim to study therapeutically relevant proteins that elicit their function solely by interacting with other proteins, and work towards inhibiting these protein-protein interactions (PPIs) by use of small molecules or peptidomimetics that have been prepared using innovative and elegant synthetic chemistry. Upon completion of these agents, we will then probe and assess their molecular interactions and downstream events in an in vitro environment through various experiments including fluorescence polarization and cell-based cytotoxicity assays.
Investigating the Therapeutic Potential of Grb7 Modulation
The established connection between abnormal Grb7 (human growth factor receptor bound protein 7) activity and cancer has rendered the protein a viable therapeutic target: its over-expression has been linked to various cancers, and Grb7 inhibition was shown to decrease the viability of several breast cancer cell lines, and reduce cell migration in pancreatic cancer cells. Grb7 functions as an adaptor protein by binding to its partners via its SH2 (Src Homology 2) domain, and small molecules that bind the Grb7 SH2 domain have the potential to modulate protein function by rendering the protein ineffective in binding its signaling partners. To that end, previous studies have identified 1 and 2 which selectively bind the Grb7 SH2 domain. Through rational design and the novel application of recent advances in synthetic chemistry, we intend to develop new synthetic agents based on these lead compounds. Finally, through chemical biology we will assess the efficacy of our agents as modulators of Grb7 function.
Mimetics of SH3 Domain Binders as Inhibitors of Protein Signaling
SH3 (Src Homology 3) domains are integral to intracellular signaling in their role as recognition motifs among binding partners. SH3 domains bind proline rich motifs that adopt a polyproline-type II helix (PPII) among two adjacent proline residues. The role of SH3 domains as mediators of protein-protein interactions has led to their extensive study in tyrosine kinase signaling, transcription and endocytosis. However, to date, few studies have been undertaken to develop selective binders of SH3 domains. Recently, Schmalz et al. successfully prepared a PPII mimetic by synthesizing a tri-cyclic moiety. Expanding upon this approach, we plan to develop other tri-cyclic PPII mimetics through the use of novel synthetic chemistry, and assess their efficacy through in vitro assays.
Intracellular Signaling Regulated by Dimeric Binders of the Grb2 SH2 Domain
Inhibition of Grb2 function has been established as a therapeutically relevant objective due to the correlation between the protein’s over-expression and the proliferation of several cancerous cell lines. A recent breakthrough study revealed the protein’s key role as an active regulator in the fibroblast growth factor receptor 2 (FGFR2) signaling events that lead to cell proliferation, migration and differentiation. The newly discovered pathway implicates Grb2 homodimers as regulators of FGFR2 signaling via Grb2 binding to the receptor’s intracellular domain, thereby inhibiting hyper-active kinase activity. Through the development of linking Grb2 homodimers via engagement of both SH2 domains, we propose a novel modality for inhibiting the cellular events that lead to up-regulated FGFR2 signaling. Simultaneous binding to the dual SH2 domains of the Grb2 homodimer will prevent FGFR2 signaling by inhibiting the receptor’s phosphorylation of Grb2 and subsequent fully active state.
For more information, feel free to take a look at my full Statement of Research Interests.
Want to learn more about my research background? Feel free to navigate the links below!
In my post-doctoral work, I expanded upon my knowledge and skills in the preparation of potential drugs and the examination of their efficacy in the fields of medicinal chemistry and molecular recognition. The target of my work was the Stat3 protein; the inhibition of its function could play a key role in the treatment of numerous cancers.
While at the University of Colorado at Boulder I developed novel organic reaction methods and undertook the total synthesis of arenolide, a macrolide with intriguing stereochemistry and bioactivity. My graduate work instilled in me a love for complex and elegant organic synthesis, which remains a hallmark of my current research interests.
“Applying Small Molecule STAT3 Protein Inhibitors as Pancreatic Cancer Therapeutics”. Arpin, C. C.; Mac, S.; Jiang, Y.; Cheng, H.; Page, B. D. G.; Kamocka, M. M.; Haftchenary, S.; Su, H.; Todic, A.; Ball, D.; Rosa, D. A.; Lai, P.-S.; Gómez-Biagi, R. S.; Ali, A. M.; Kerman, K.; Fishel, M. L.; Gunning, P. T. Molecular Cancer Therapeutics 2015, accepted with revisions.
“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, A. M.; Lewis, A. M.; 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, in press.
“A Novel Small Molecule STAT inhibitor, PG-S3-004 inhibits myeloma growth in vivo and enhances the activity of bortezomib”. Croucher, D.; Page, B. D. G.; Li, Z.; Wei, E.; Jimenez-Zepeda, V. H.; Arpin, C. C.; Gunning, P. T.; Trudel, S. Blood, submitted January 2015.
“Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia”. Eiring, A. M.; Page, B. D. G.; Kraft, I. L.; Mason, C. C.; Vellore, N. A.; Resetca, D.; Zabriskie, M. S.; Zhang, T. Y.; Khorashad, J. S.; Engar, A. J.; Reynolds, K. R.; Anderson, D. J.; Senina, A.; Pomicter, A. D.; Arpin, C. C.; Ahmad, S.; Heaton, W. L.; Tantravahi, S. K.; Todic, A.; Colaguori, R.; Moriggl, R.; Wilson, D. J.; Baron, R.; O’Hare, T.; Gunning, P. T.; Deininger, M. W. Leukemia 2014, 29, 586-597. DOI: 10.1038/leu.2014.245
“Progress towards the development of SH2 domain inhibitors”. Arpin, C. C.; Kraskouskya, D.; Duodu, E.; Gunning, P. T. Chemical Society Reviews 2013, 42, 3337-3370. DOI: 10.1039/C3CS35449K
“The Total Synthesis of Dermostatin A”. Zhang, Y.; Arpin, C. C.; Cullen, A. J.; Mitton-Fry, M. J.; Sammakia, T. Journal of Organic Chemistry 2011, 76 (19), 7641-7653. DOI: 10.1021/jo2012658
“New Inhibitors of Colony Spreading in Bacillus subtilis and Bacillus anthracis”. Hao, X.; Nguyen, T.; Kearns, D. B.; Arpin, C. C.; Fall, R.; Sammakia, T. Bioorganic and Medicinal Chemistry Letters 2011, 21 (18), 5583-5588. DOI: 10.1016/j.bmcl.2011.06.082