OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015)
BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors.
Follow this format for each person. DO NOT EXCEED FIVE PAGES.
NAME: Christopher Hulme
eRA COMMONS USER NAME (credential, e.g., agency login): chulme
POSITION TITLE: Professor
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training
and residency training if applicable. Add/delete rows as necessary.)
DEGREE
(if applicable)
Completion
Date
MM/YYYY
FIELD OF STUDY
Hertford College, Oxford University
BA
06/1989
Chemistry
Hertford College, Oxford University
D.Phil
07/1992
Chemistry
Postdoc
08/1994
Chemistry
INSTITUTION AND LOCATION
University of Texas at Austin
A. Personal Statement
I have built and run several high-throughput medicinal chemistry organizations in industry and transitioned to
an academic role in late 2007. I have managed portfolios of targets spanning the value chain in drug discovery
from hit generation to progression of molecules into man and as such managed teams that produced early
development candidates for PDEIV (Rhone-Poulenc Rorer) and VR-1 (Amgen). In total, it is estimated that
60+ targets of interest have passed through my organizations, spanning a multitude of therapeutic areas that
include oncology, metabolic disorders, inflammation, pain, and neurodegeneration. As Director of BIO5
Medicinal Chemistry, I have the resources and extensive infrastructure in place to initiate and significantly
progress the translational campaign detailed herein – establishment of the latter center was made feasible
through the successful award of a GO grant in 2010. More specifically, CNS projects previously falling under
my jurisdiction include the development of inhibitors of JNK-3 for stroke (Amgen), MCHr for obesity (Amgen),
Pyk-2 for the treatment of brain gliomas (University of Arizona) and BACE for Alzheimer’s (Lilly). A significant
number of other kinases were also part of prior industrial portfolios I ran, including JNK-1, PKB, Aurora A/B and
Plk-1, and preliminary collaborations at the University of Arizona and Yale include targeting Plk-4, ROCK and
aPKC. Indeed, the PI is well versed in addressing the need for molecular pre-requisite physico-chemical
properties that enable passive BBB penetration and minimization of residence time in the BBB lipid bi-layer to
dial out potential pGP efflux liabilities. In summary, I have been involved in kinase research for ~ 20 years,
being a co-author on one of the very early medicinal chemistry reviews in the field. The DYRK1A collaboration
with Dr. Travis Dunckley has been active for more than three years although needs sustained funding to build
on the significant progress to date. Recent reviews by the collaborators detail the state-of-art relevance of the
target and current inhibitor design, and emerging indications for Glioblastoma are being investigated. In short, I
am extremely qualified to pursue members of the kinase target-family in the neurodegeneration field and this
is supplemented by my national/international reputation in high-throughput medicinal chemistry and file
enhancement arenas.
1. Myers, M.R.; Hei, W.; Hulme, C. (1997). Inhibitors of Tyrosine Kinases Involved In Inflammation and
Autoimmune Disease. Current Pharmaceutical Design, 3, 463-492.
2. 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 Chemical Neuroscience, 3, 857-872.
3. Medda, F.; Smith, B.; Gokhale, V.; Shaw, A.; Dunckley, T.; Hulme, C. (2013). Beyond Secretases: Kinase
Inhibitors for the treatment of Alzheimer’s Disease? Annual Reports in Medicinal Chemistry, 48, 57-71.
4. Kusne, Y.; Xu, Z.; Dietrich, J.; Hulme, C.; Ghoush, S. (2014). Targeting aPKC simultaneously disables
cell autonomous and non-cell autonomous oncogenic signaling in GBM. Science Signaling, 7(338),
ra75/1-ra75/15, 15 pp
B. Positions and Honors
Positions and Employment
1994–1996
Research Scientist, Rhone-Poulenc Rorer, Collegeville, PA.
1996–1997
Senior Research Scientist, Rhone-Poulenc Rorer, Collegeville, PA.
1997–1998
Research Fellow, Rhone-Poulenc Rorer, Collegeville, PA.
1999–2004
Head of High-Throughput Medicinal Chemistry, Amgen, Thousand Oaks, CA.
2004–2007
Head of High-Throughput Medicinal Chemistry, Eli Lilly, Indianapolis, IN.
2007–2010
Associate Professor, University of Arizona, Tucson, AZ.
2010–
Professor Medicinal Chemistry, University of Arizona, Director BIO5 Medicinal Chemistry
Tucson, AZ.
Other Experience and Professional Memberships
1997–
Ad hoc reviewer for more than 30 journals.
1999–
ACS member (American Chemical Society).
2003–
Editorial Advisory Boards of Current Organic Synthesis/ARKIVOC/Open Drug Discovery.
2004–2011
IUPAC Affiliate Member.
2005
Member Study Section P41 Pilot Scale Libraries.
2007–
AACP Member (American Association of Colleges of Pharmacy).
2007–2011
Associate Editor, Molecular Diversity.
2007–
Arizona Bioindustry Association (AZBio) member.
2008
Member of Special Emphasis Panel July 2008: NIH renewals for “Centers of Excellence in
Chemical Methodologies and Library Development (CMLD).”
2008
Synthetic and Biological Chemistry B Study Section, October 2008.
2009
SBIR Study Section, October 2009, 2010.
2009
Session Chair. Mastering Medicinal Chemistry, Feb’ 25-27, San Francisco.
2009
Member External Advisory Board, SPORE lung cancer initiative, University of Louisville.
2010
Ad hoc Special Emphasis Panel (P01 grant renewals).
2011
Editor: Special Edition on Multi-Component reactions, MODI.
2011
R19 study section.
2012
Host & Chair, ACS National Medicinal Chemistry Conference, Oro Valley, AZ
2012–2014
NWO Grant Reviewer.
2014
University of Kansas KOBRE Drug Discovery Grant External Reviewer.
2014–
Editorial Board Member “Central Nervous System Agents in Medicinal Chemistry”
2015
Session Chair: MCR2015, Brasilia, Brazil.
2015
ANR Grant Reviewer.
Honors
2006
2007–2008
2011
2012
Lilly Award for Excellence in File Enhancement.
Abbott Laboratories New Faculty Award for Creativity in Organic Chemistry.
University of Arizona Leading Edge Researcher 2011.
Host: 2012 ACS National Medicinal Chemistry Conference, Oro Valley, AZ.
C. Contribution to Science
1. The discovery and development of PDEIV Inhibitors for RA: This translational campaign was performed
at RPR from 1994-1997, prior to the explosion in the discovery of numerous additional PDEs and splice
variants. Indeed, at this time the PDE isoforms PDEIVA and B had not been identified, however anti-TNF
therapies toward RA where clearly being strongly validated through monoclonal antibody approaches to
sequester this pivotal pro-inflammatory cytokine. An effort was underway to support RP73401 (Phase III) with
back-up candidates. I personally lead a team of scientists that developed ~ 5 new series of molecules, with
potent inhibitory activity against PDEIV and functional activity in cells as measured by reduction in TNF-
production. The most promising was progressed to show enticing in vivo efficacy in a SCW induced arthritis
model (ED50 23mg/kg, b.i.d, p.o.) with high oral bioavailability (96%). The compound reached an early
development candidate milestone and was being moved forward, until the inflammation/immunology franchise
was re-directed to metabolic disorders.
a. Hulme, C., Moriarty, K., Huang, F-C., Souness, J. & Djuric, S.W. (1998). Quaternary Substituted PDE4
Inhibitors II: Novel Series of -lactams. Bioorganic Medicinal Chemistry Letters, 8, 399.
b. Hulme, C., Mathew, R., Moriarty, K., Souness, J., Cox, P., Uhl, J., & Djuric, S.W. (1998). The Synthesis
and Biological Evaluation of a Novel Series of Indole PDEIV Inhibitors. Bioorganic Medicinal Chemistry
Letters, 8, 1867.
c. Hulme, C., Mathew, R., Moriarty, K., Souness, Uhl, J., Huang, F-C., & Djuric, S.W. (1998). Orally
Active Indole N-Oxide PDEIV Inhibitors. Bioorganic Medicinal Chemistry Letters, 8, 3053.
2. Studies in File Enhancement – the discovery of UDC (Ugi/Deprotect/Cyclize): Tasked with the
generation of large 5 to 10,000 members, with an initial focus of discovering small molecule PTHr agonists, I
led group of five scientists initiating studies in the relatively obscure field of multi-component reactions (RPR).
Efforts continued for an additional two years whilst head of HTMC at Amgen. During the course of this work,
the concept of employing post-condensation modifications of MCR adducts was introduced to the scientific
community at large with a series of seminal papers and highly cited reviews which spawned worldwide efforts
in generating molecular diversity via new MCRs and modifications of their adducts thereafter. Published
protocols from these efforts have been extensively employed by academics, the private sector and CROs in
the hit discovery phase and beyond, delivering a plethora of published probes, leads and at least two examples
[(i) Aplaviroc, GSK, CCR5 antagonists for HIV infection, Phase II] and [GSK, Oxytocin antagonists for pre-term
labor, Phase II] where initial hits were discovered using these one-pot protocols and rapidly progressed along
the value chain without the need to scaffold-hop to deliver an IND ready candidate. The work in this period
afforded the shortest known routes to many known, pharmacologically relevant chemotypes and unique
scaffolds.
a. Hulme, C., Tang, S. C. Burns, C., & Labaudiniere, R. (1998). Improved Procedure for the Solution
Phase Synthesis of 1,4-Benzodiazepines-2,5-dione Libraries via the Ugi reaction and Armstrong’s
Convertible Isonitrile. Journal of Organic Chemistry, 63, 8021.
b. Hulme, C., Ma, L., Romano, J., Morton, G., Tang, S-Y., Cherrier, M-P., Choi, S., & Labaudiniere, R.
(2000). Novel Applications of CO2/MeOH for the Synthesis of Hydantoins and Cyclic Ureas via the Ugi
Reaction. Tetrahedron Letters, 41, 1883.
c. Hulme, C., & Gore, V. (2003). Multi-component Reactions: Emerging Chemistry in Drug Discovery.
Current Medicinal Chemistry, 10, 151.
3. Molecular Diversity Generation - the establishment of the Arizona Compound Collection: This work
took place in academia under the auspices of a milestone driven GO grant to establish infrastructure,
personnel, HTS screening capabilities, an internal compound collection (> 30,000 cpds) and to screen for
activity against the Androgen receptor. Such a centralized coordinated effort was previously absent in the
Arizona research arena. My role as PI was to coordinate build phase and direct a group of 13 scientists,
comprised of medicinal chemists, computational and analytical support scientists. During the course of the
work, concepts detailed in section 2 were elaborated into more complex, cascade/MCR driven molecular
diversity methodologies to enhance the collection which have not only delivered ligands and probes for study
at the UA, but spurred additional efforts in the organic MCR community. All stretch goals were fulfilled which
has galvanized the health sciences community at the UA and libraries of small molecules, both targeted and
diverse sets, are now being screened, delivering bona-fide starting points for translational campaigns across a
variety of therapeutic areas, most relevant in the oncology arena.
a. Xu, Z., De Moliner, F., Cappelli, A., Hulme, C. (2012). Ugi/Aldol Sequence: Expeditious Entry to
Several Families of Densely Substituted Nitrogen Heterocycles. Angewandte Chemie International
Edition, 51, 8037-8040.
b. Hulme, C., Petit, J., Mousses, S., Yin, H., Dietrich, J., Meurice, N. (2010) Formation of the Southwest
Comprehensive Center for Drug Discovery and Development: New technologies, organization, work
flow and projections. Abstracts of Papers, 239th ACS National Meeting, San Francisco, CA, United
States, March 21-25, MEDI-70.
c. Ariza, G.M., Ayaz, M., Medda, F., Hulme, C. (2014). Synthesis of diverse nitrogen-enriched
heterocyclic scaffolds using a suite of tunable one-pot multicomponent reactions. Journal of Organic
Chemistry, 79, 5153-5162.
4. Development of Androgen receptor antagonists: Highly noteworthy is the discovery (unpublished
structures) of novel AR antagonists for the treatment of CRPC emanating from efforts in section 3. Prostate
cancer will shortly be the leading killer of males in the US and the prognosis for CRPC is poor. New treatments
continue to suffer from the development of resistance due to point mutations in the AR ligand binding domain.
Molecules discovered from the screening campaign, combined with rapid SAR development have led to leads
with better affinity for the AR receptor than Enzalutamide, with ~ equivalent functional activity in reporter
assays and slightly superior activity in 3 prostate-specific cell lines (cell viability assays). Current lead
molecules are significantly less toxic than Enzalutamide in AR negative DU145 cells and exist in distinct
‘chemical space’, being derived from a one pot synthetic protocol. Formulation and in vivo studies are being
scheduled. These findings may lead to a superior version of the Enzalutamide (approved 2012). Collaborations
in the Arizona cancer center have been pivotal in pushing this project forward.
a. Shaw, A.Y., Gokhale, V., Stratton, S.P., Hulme, C. (2014). Promising, early stage novel Androgen
receptor antagonists in head-head comparisons with Enzalutamide and Bicalutamide. Abstract of
Papers #2524, AACR Meeting Abstracts, San Diego, CA, April 5-9.
b. Ariza, G.M., Hulme, C. (2015). Recent advances in allosteric androgen receptor inhibitors for the
potential treatment of castration-resistant prostate cancer. Pharmaceutical Patent Analyst, in press.
5. VR-1 Inhibitors for the treatment of neuropathic pain: This research was conducted at Amgen where I
was responsible for a group of 15 scientists. VR-1 (vannilloid receptor 1) has been implicated with neuropathic
pain. Originally it was capsaicin action that provided evidence for the existence of specific “vanilloid” receptors.
As part of a larger group, a sub-set of six chemists from the HTMC group under my direction joined the effort
delivering several series of unique VR-1 antagonists, demonstrating exquisite potency, leading to extensive
pre-clinical optimization and delivery of an early development candidate. Although losing its position now as a
premier target for neuropathic pain, in 2003, this ion channel was at the forefront of extensive drug hunting
efforts and this group was one of the first in the field.
a. Hulme, C., Ncube, M. V., Norman, M. H., Ognyanov, V. I., Pettus, L. H., Wang, X., Zhu, J. (2005)
Vanilloid receptor ligands and their use in treatments. U.S. Pat. Appl. Publ. US 20050165046 A1
20050728 AN 2005:672886.
b. Hulme, C., Ncube, M. V., Norman, M. H., Ognyanov, V. I., Pettus, L. H., Wang, X., Zhu, J. (2005)
Vanilloid receptor ligands and their use in treatments. U.S. Pat. Appl. Publ., US 20050165049 A1
20050728 AN 2005:672887.
Complete List of Published Work in My Bibliography:
http://www.ncbi.nlm.nih.gov/sites/myncbi/1voPlM13Ib5m/bibliography/47991914/public/?sort=date&direction=ascending
D. Research Support
Ongoing
5R01 CA138702
(Meuillet, PI)
07/01/10–06/30/16
NIH/NCI
Inhibition of Novel Molecular Targets of Prostaglandin Formation for Anti-tumor Activity.
The overall goal of the proposal is to develop novel strategies and agents for the improved treatment of colon
cancer via modulation of PGE2 levels.
Role: Co-Investigator
Completed
No Grant #
(Hulme PI)
06/01/12–07/01/13
UA BIO5 Drug Discovery Grant
Discovery and Development of DRK1A inhibitors for Neurodegenerative Disorders
The goal of this proposal was to improve affinity of low uM DRYK1A inhibitors and modulate physicochemical propertie
to enhance small molecule cell permeability for evaluation in a cell tau phosphoryation assay with the goal of garnering
sustained funding for development of small molecule therapeutics for neurodegenerative diseases.
5P41 GM086190
(Hulme PI)
08/05/10–05/31/14
NIH/NIGMS
Expeditious, Biologically Driven Pilot Libraries for File Enhancement
The aim of this application was to produce novel pilot-scale libraries for evaluation via the Molecular Library
Screening Network (MLSCN).