Christopher Hulme

Christopher Hulme

Professor, Pharmacology and Toxicology
Professor, BIO5 Institute
Primary Department
Department Affiliations
Contact
(520) 626-5322

Work Summary

The Hulme group is focused on small molecule drug design and developing enabling chemical methodologies to expedite the drug discovery process. The development of small molecule inhibitors of kinases is of particular interest.

Research Interest

Christopher Hulme, PhD, focuses on small molecule drug design and developing enabling chemical methodologies to expedite the drug discovery process. Target families of particular current interest for the group are kinases, protein-protein interactions and emerging DNA receptors for indications in oncology. Such efforts are highly collaborative in nature and students will be exposed to the full array of design hurdles involved in progressing molecules along the value chain to clinical evaluation. These efforts will be aided by the group’s interest in both microwave assisted organic synthesis (MAOS) and flow chemistry. Both technologies enable ‘High-throughput Medicinal Chemistry’ (HTMC) and will be supported by similar High-throughput Purification capabilities.The group also has a long standing interest in the development of new reactions that produce biologically relevant molecules in an efficient manner. Front loading screening collections with molecules possessing high ‘iterative efficiency potential’ is critical for expediting the drug discovery process. The discovery of such tools that perturb cellular systems is of high value to the scientific community and may be facilitated by rapid forays into MCR space that can produce a multitude of novel scaffolds with appropriate decoration for evaluation with a variety of different screening paradigms.Novel hypervalent iodine mediated C-H activation methodologies is also an active area of interest. Probing the scope of the transformation below and investigating applications toward the synthesis of new peptidomimetics will be an additional pursuit in the Hulme group.

Publications

Hulme, C., Branca, C., Shaw, D., Belfiore, R., Gokhale, V., Shaw, A., Foley, C., Dunckley, T., Cacomol, A., & Oddo, S. (2016). Dyrk1 inhibition improves Alzheimer’s disease-like pathology.. Molecular Degeneration.

Note: this paper required a year long legal agreement as the in vivo pharmacologist refused to release the data unless we agreed to give him 10% equity in any value creation and sole starred authorship on the first paper. Under any normal circumstances I would have been lead author on this paper. A revision was requested as the structure of the molecule is not being revealed at this stage.

Bienaymé, H., Hulme, C., Oddon, G., & Schmitt, P. (2000). Maximizing synthetic efficiency: Multi-component transformations lead the way. Chemistry - A European Journal, 6(18), 3321-3329.

Abstract:

With the emergence of high-throughput screening in the pharmaceutical industry in the early 1990's, organic chemists were faced with a new challenge: how to prepare large collections of molecules (the libraries) to "feed" the high-throughput screen? The unique exploratory power of some reactions (such as the 40 year-old Ugi four-component condensation) was soon recognized to be extremely valuable to produce libraries in a time-and cost-effective manner. Over the last five years, industrial and academic researchers have made these powerful transformations into one of the most efficient and cost-effective tools for combinatorial and parallel synthesis.

Meurice, N., Wang, L., Lipinski, C. A., Yang, Z., Hulme, C., & Loftus, J. C. (2010). Structural conservation in band 4.1, ezrin, radixin, moesin (FERM) domains as a guide to identify inhibitors of the proline-rich tyrosine kinase 2. Journal of Medicinal Chemistry, 53(2), 669-677.

PMID: 20017492;PMCID: PMC3178892;Abstract:

The nonreceptor focal adhesion kinases FAK and Pyk2 play a central role in the regulation of glioma cell proliferation and migration, making them attractive targets to improve clinical outcome. Noncatalytic targeting represents a novel approach to regulate the activity of these tyrosine kinases. A combination of site directed mutagenesis and molecular modeling was used to identify compounds that target the F3 module of the Pyk2 FERM domain. A protein pharmacophore model for the Pyk2 FERM/F3 module, generated utilizing the structural conservation of ligand-bound FERM domains with known 3D structures, was used to search the LeadQuest compound library. Compounds compliant with the model were tested for their ability to inhibit the binding of a monoclonal antibody that maps to a functional site on the F3 module. The highest scoring compound bound directly to the Pyk2 FERM domain, inhibited Pyk2 stimulated glioma migration, and provides the framework for the development of novel therapeutic agents to target the activity of the focal adhesion kinases. ©2009 American Chemical Society.

Hulme, C., Medda, F., Sells, E., Chang, H., Dietrich, J., Chappeta, S., Smith, B., Gokhale, V., Meuillet, E. J., & Hulme, C. -. (2013). Synthesis and biological activity of aminophthalazines and aminopyridazines as novel inhibitors of PGE2 production in cells. Bioorganic & medicinal chemistry letters, 23(2).

This Letter reports the synthesis and biological evaluation of a collection of aminophthalazines as a novel class of compounds capable of reducing production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 28 analogs were synthesized, assayed for PGE(2) reduction, and selected active compounds were evaluated for inhibitory activity against COX-2 in a cell free assay. Compound 2xxiv (R(1)=H, R(2)=p-CH(3)O) exhibited the most potent activity in cells (EC(50)=0.02 μM) and minimal inhibition of COX-2 activity (3% at 5 μM). Furthermore, the anti-tumor activity of analog 2vii was analyzed in xenograft mouse models exhibiting good anti-cancer activity.

Hulme, C., Chappeta, S., & Dietrich, J. (2009). A simple, cheap alternative to 'designer convertible isonitriles' expedited with microwaves. Tetrahedron Letters, 50(28), 4054-4057.

Abstract:

Interest in designer convertible isonitriles has increased in recent years with the growing recognition that isonitrile-based multi-component reactions (IMCRs) are highly effective in rapidly accessing, new and pharmacologically relevant diversity space. This Letter reports on the novel use of n-butylisonitrile as a cheaper and more atom-economical alternative to currently reported 'designer convertible isonitriles', facilitated by the advent of microwave-assisted organic synthesis (MAOS).