Christopher Hulme
Professor, BIO5 Institute
Professor, Pharmacology and Toxicology
Primary Department
Department Affiliations
(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

Baldwin, J. E., Hulme, C., Schofield, C. J., & Edwards, A. J. (1993). Synthesis of potential β-turn bicyclic dipeptide mimics. Journal of the Chemical Society - Series Chemical Communications, 935-936.
Dietrich, J., Hulme, C., & Hurley, L. H. (2010). The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: A structural analysis of the binding interactions of Gleevec ®, Nexavar®, and BIRB-796. Bioorganic and Medicinal Chemistry, 18(15), 5738-5748.

PMID: 20621496;Abstract:

The majority of kinase inhibitors developed to date are competitive inhibitors that target the ATP binding site; however, recent crystal structures of Gleevec® (imatinib mesylate, STI571, PDB: 1IEP), Nexavar ® (Sorafenib tosylate, BAY 43-9006, PDB: 1UWJ), and BIRB-796 (PDB: 1KV2) have revealed a secondary binding site adjacent to the ATP binding site known as the DFG-out allosteric binding site. The recent successes of Gleevec® and Nexavar® for the treatment of chronic myeloid leukemia and renal cell carcinoma has generated great interest in the development of other kinase inhibitors that target this secondary binding site. Here, we present a structural comparison of the important and similar interactions necessary for Gleevec®, Nexavar®, and BIRB-796 to bind to their respective DFG-out allosteric binding pockets and the selectivity of each with respect to c-Abl, B-Raf, and p38α. A structural analysis of their selectivity profiles has been generated from the synthesis and evaluation of 8 additional DFG-out allosteric inhibitors that were developed directly from fragments of these successful scaffolds. © 2010 Elsevier Ltd.

Medda, F., & Hulme, C. (2012). A facile and rapid route for the synthesis of novel 1,5-substituted tetrazole hydantoins and thiohydantoins via a TMSN 3-Ugi/RNCX cyclization. Tetrahedron Letters, 53(42), 5593-5596.

Abstract:

This Letter describes novel methodology for the rapid assembly of new and biologically appealing 1,5-substituted tetrazole-hydantoins and thiohydantoins. The product of a TMSN 3-Ugi multi-component reaction is treated with an excess of isocyanate or isothiocyanate to generate the final scaffold in moderate to good yields. The applicability of this solution phase methodology to the preparation of a small collection of compounds is discussed. © 2012 Elsevier Ltd. All rights reserved.

Magnus, P., Roe, M. B., Lynch, V., & Hulme, C. (1995). The structure of a stable new organotellurium azide: Bis- azidodiphenyltellurium(IV) oxide. Journal of the Chemical Society, Chemical Communications, 1609-1610.

Abstract:

Diphenyltelluroxide reacts with azidotrimethylsilane to give a remarkable stable adduct (Ph2TeN3)2O which was characterised by X-ray crystallography.

Tempest, P., Pettus, L., Gore, V., & Hulme, C. (2003). MCC/SNAr methodology. Part 2: Novel three-step solution phase access to libraries of benzodiazepines. Tetrahedron Letters, 44(9), 1947-1950.

Abstract:

New developments in the search for novel pharmacological agents over the last decade have focused on the preparation of chemical libraries as sources for new leads for drug discovery. To aid this search a plethora of personal synthesizers and new automation technologies have emerged to help fuel the lead discovery engines of drug discovery organizations. In fact, multi-step solid-phase syntheses of diverse libraries in excess of 10,000 products are now feasible via split and mix techniques. At the same time, a multitude of more efficient, diversity or target oriented solution phase chemical methodologies have appeared in the chemical literature, which have enabled the relatively facile construction of successful lead generation libraries with low FTE input and little capital expenditure. This communication reveals a further application of N-BOC-α-aminoaldehydes in the Ugi condensation reaction, followed by a secondary SNAr cyclization, accessing arrays of biologically relevant benzodiazepines in good yield and overall purity. © 2003 Elsevier Science Ltd. All rights reserved.