Christopher Hulme

Christopher Hulme completed his D.Phil at Oxford University. Subsequently, he spent 15 years in big pharma, holding positions as head of High-throughput Medicinal Chemistry and Global Head of Platform Library Sciences, spanning RPR, Amgen & Eli Lilly. As such, he established targeted and diversity-oriented screening collections, engaging in over 60 hit-lead and multiple lead optimization campaigns. He joined the University of Arizona in 2007 and has garnered in excess of $20 million during this tenure from public and private sources. Currently, his lab is focused on small molecule and targeted protein degradation discovery paradigms. In particular, the development of small molecule kinase inhibitors is of interest. In 2018 he co-founded Iluminos Therapeutics, currently pushing forward Dyr533 into IND enabling studies for the treatment of Down Syndrome and Alzheimer's Disease through selective inhibition of the kinase Dyrk1a. More recently, with a significant venture capital investment, Dr Hulme co-founded the start-up Branch Therapeutics LLC, whose primary mission is the development of multi-targeted kinase inhibitors towards colo-rectal cancer. The Hulme group trains bona fide student drug hunters in the art of medicinal chemistry and efforts span hit generation through SAR/SPR optimization, in vivo studies and latterly extensive interactions with CDMOs for GLP drug substance manufacturing on a kilo scale. We are always actively looking for students with a strong background in organic chemistry.

1. Therapies for Alzheimer’s and Neurodegenerative Diseases
With 24.3 million people affected in 2005 and an estimated rise to 45 million in 2020, dementia is currently a leading unmet medical need and a costly burden on public health. Seventy percent of these cases have been attributed to Alzheimer’s disease (AD), a neurodegenerative pathology whose most evident symptom is a progressive decline in cognitive functions. Studies in the group focus on providing a significant mechanistic alternative to common approaches that solely focus on small molecule design toward APP-cleavage inhibition. In particular, ongoing efforts are aimed at the design of structurally novel small molecule inhibitors of the dual-specificity tyrosine phosphorylation–regulated kinase 1A (DYRK1A) and their evaluation of in vivo activity and measurement of in vivo tau phosphorylation and neurofibrillary tangles pathology in 3X-TgAD mouse models of AD. Moreover, DYRK1A has also been suggested to affect other cellular pathways that may be involved in mental impairment and neurodegenerative dementia.

Studies are being conducted with a long-term collaborator (Dr. Travis Dunckley) at Translational Genomics (TGen). Inhibition of DYRK1A functioning should theoretically mitigate multiple processes underlying the progression of neurodegeneration, particularly in the AD-related therapeutic area, for which key DYRK1A substrates include: (1) tau protein, (2) amyloid precursor protein, and (3) presenilin 1 (the catalytic subunit of γ-secretase), all pointing to clear mechanisms through which elevated DYRK1A activity may be promoting AD progression. Several other AD-related kinases are targets of current interest in the group (Smith B, Medda F, Gokhale V, Dunckley T, Hulme C [2012] Recent Advances in the Design, Synthesis, and Biological Evaluation of Selective DYRK1A Inhibitors: A New Avenue for a Disease Modifying Treatment of Alzheimer’s. ACS Chem. Neurosci., DOI: 10.1021/cn300094k).

2. Therapeutics Modulating Prostaglandin E₂Production
Prostaglandin E₂ (PGE₂) is well known to play a pivotal role in processes associated with inflammation, pain, and pyresis and is over-expressed in various tumors where chronic inflammation has been linked to the growth of various cancerous tissues. Indeed, PGE₂ has been identified as the major prostaglandin associated with the progression of various tumor malignancies, including that of the colon, lung, and breast. An ongoing project within the group is the development of novel small molecules that mitigate PGE₂ production and display antitumor growth properties in vivo. Several novel series of small molecules have been developed and are under further investigation (Smith B, Chang HH, Medda F, Gokhale V, Dietrich J, Davis A, Meuillet EJ, Hulme C [2012] Synthesis and biological activity of 2-aminothiazoles as novel inhibitors of PGE₂ production in cells. Bioorg. Med. Chem. Lett., 22:3567–3570).

3. Enabling Chemical Methodologies
a. Applications of Multi-Component Reactions
The group also has a long-standing interest in the development of new reactions that produce biologically relevant molecules in an efficient manner. Indeed, front-loading screening collections with molecules possessing high “iterative efficiency potential” is critical for expediting the drug discovery process. Compounds derived from multi-component reactions (MCRs) demonstrate such potential, and thus their discovery and applications are of utmost importance. Closely linked with the Molecular Libraries Small Molecule Repository, the group seeks to develop an operationally friendly chemistry that delivers products of high molecular diversity that ultimately enable library production and deposition of compounds in both national and local screening collections. A one-pot five-step transformation developed in the group is depicted (Xu Z, De Moliner F, Cappelli A, Hulme C [2012] Ugi/Aldol Sequence: Expeditious Entry to Several Families of Densely Substituted Nitrogen Heterocycles. Angewandte Chem., Int. Ed., 51:8037–8040).

Recent discoveries in the group have facilitated a new project toward the expeditious syntheses and application of novel dendrimer families, repetitively branched molecules that show high promise in drug delivery, gene delivery, and sensor technologies.

b. New Hypervalent Iodine Methodology and Applications
Novel hypervalent iodine–mediated C-H activation methodologies and their application for the preparation of novel peptidomimetics are an active area of research.

c. Organoselenium Chemistry
A recent discovery of a new selenium dioxide–mediated oxidative amidation is driving new studies in molecular diversity generation.

Publications

Small molecule inhibitors of dyrk/clk and uses thereof C Hulme, C Foley - US Patent App. 18/796,015, 2025

Tandon V, Fistrovich A, Nogales J, Ferro F, Rokey SN, Cabel C, Miller AD, Yagel M, Duncan C, Atmasidha A, et al. 2025 Mar. Dyr726, a brain-penetrant inhibitor of PI3Kα, Type III receptor tyrosine kinases, and WNT signaling. doi:10.1101/2025.03.26.645490. 

Wilms G, Schofield K, Maddern S, Foley C, Shaw Y, Smith B, Basantes LE, Schwandt K, Babendreyer A, Chavez T, et al. 2024. Discovery and Functional Characterization of a Potent, Selective, and Metabolically Stable PROTAC of the Protein Kinases DYRK1A and DYRK1B. Journal of Medicinal Chemistry. 67(19):17259–17289. doi:10.1021/acs.jmedchem.4c01130. 

Deuterated Multi-Component Reactions Affording Site-specific Deuterium Labeled Products. Schofield, K.; Maddern, S.; Zhang, Y.; Wang, W.; Knight, R.; Galligan, J.; Hulme, C. Beilstein. J. Org. Chem., 2024, 20, 2270-2279. 

Kinase-independent activity of DYRK1A promotes viral entry for highly pathogenic human coronaviruses. Strine, M.; Cai, W.; Wei, J.; Alfajaro, M.; Filler, R.; Biering, S.; DeWeirdt, P.; Schofield, K.; Hulme, C.; Konermann, S.; Doench, J. G.; Hsu, P. D.; Wilen, C. B.  PLOS Biology, 2023, 21(6), e3002097. 

The Omnipresence of DYRK1A in Human Diseases Deboever, E.; Fistrovich, A.H.; Hulme, C.; Dunckley, T. Int. J. Mol. Sci., 2022, 23, 9355. 

Martinez-Ariza G, Hulme C. 2015. Recent advances in allosteric androgen receptor inhibitors for the potential treatment of castration-resistant prostate cancer. Pharm Pat Anal. 4:387–402. doi:10.4155/ppa.15.20.

Awards

• James Halpert Research Award
  • College of Pharmacy, Winter 2022
• Student's Choice Award
  • Phoenix Cohort P2, Summer 2019
• Certificate of Recognition
  • ACS Publications, Summer 2017
• Angewandte Chemie, top 5% reviewer of the year
  • Angewandte Chemie, Wiley, Fall 2016
• 2011 Leading Edge Researcher Award
  • University of Arizona, Spring 2011
• Abbott New Faculty Award for creativity in Organic Synthesis
  • Abbott Labs, Summer 2008
  • Abbott Labs, Fall 2007