Transcript Poster: Translational Drug Development

Translational Drug Development: Research that Takes you From Bench to Bedside and Beyond
Professor Hong-yu Li, [email protected], 501-296-1154
Introduction
Target Identification
and Validation
Cloning-Expression
and Verification
Preclinical
Development
Compound Synthesis
and Evaluation
Lead Optimization
Biological Testing
Computer Aided Drug Discovery
One of the most common techniques in drug design is Computer Aided Drug Discovery
(CADD). Computational screening of virtual libraries against validated targets permits the
rapid identification of starting points for synthetic libraries and identifies key ligand
interactions within the binding pocket. We use CADD to accelerate our medicinal
chemistry efforts and to investigate binding activity to increase the potency and selectivity
of hit compounds.
Li, et al., Organic & Biomolecular Chemistry, 2015.
Li, et al., Synlett, 2014.
Novel One-Pot, Cascade Reactions
Cascade reactions are an essential part to synthetic medicinal chemistry because they
permit the ability to carry out multi-step reactions simultaneously. This limits the amount
of time spent on purification and analytical analysis, and expedites the production of final
compounds. In Professors Li’s laboratory, you will have the opportunity to develop novel
cascade reactions to reach target molecules.
Li, et al., Organic Letters, 2014.
Li, et al., Tetrahedron Letters, 2014.
Novel Multicomponent Reactions
Multicomponent reactions (MCRs) permit the generation of rapid chemical diversity from
commercially available starting materials. In a simple one-pot modality, highly complex
drug-like molecules can be generated. In Professors Li’s laboratory, you will have the
opportunity to develop novel MCR chemistries.
Li, et al., European Journal of Medicinal Chemistry, 2014.
Li, et al., European Journal of Medicinal Chemistry, 2015.
Privileged Fragment-Based Drug Discovery
Traditional fragment-based drug discovery utilizes low molecular weight compounds, or
‘fragments’, to determine low-affinity binding to a target. The fragments are then
assembled into a full-length, high-affinity inhibitor. We utilize privileged fragment-based
drug discovery to generate fragments of known biological significance based on an
endogenous ligand. Our lab has developed a privileged fragment library with well
established binding profiles to screen against targets of interest. Results from these screens
are used to further design hit molecules into validated lead candidates.
Adenine
Adenosine triphosphate (ATP)
Privileged Fragment Library
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Pz-1 was discovered in Professor Li’s
laboratory from a student's thesis. The
compound is under late-stage pre-clinical
development and has generated ~$1.75
million in contracts and grants.
Li, et al., Tetrahedron Letters, 2013.
State-of-the-Art Equipment
Teledyne Isco CombiFlash® Rf 150
Drug Discovery Success Stories
Synergistic Medicinal Chemistry
Low-hanging drug targets have been heavily
exploited and potential for target breakthroughs
is rare. To excel in an inundated market, we
generate 'smart-drugs' that are capable of
shutting down multiple pathways that promote
human disease. Instead of drug-repurposing, we
have established the concept of 'targetrepurposing'. We identify drug targets that
display cooperation in a variety of disease
states. We then generate highly advanced
candidates to shut down these targets in a
balanced fashion. The technique we employ is
called SynMedChem, which is derived from
synergistic medicinal chemistry.
Modeling and
Design
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Li, et al., Angewandte Chemie, 2015.
A very difficult aspect of therapeutic development is identifying novel drug candidates
with unique structures. A pivotal strategy to generate new ‘molecular space’ is to devise
synthetic strategies that can expand molecular diversity. In Professor Li’s laboratory, you
will have the opportunity to identity new reactions that solve current synthetic limitations.
Adenine-Like Warheads
Our strategy is to develop single agent
treatment modalities that effectively shut down
multiple promoters of disease. We call this
approach Single Agent Polypharmacology, or
SAP. Our flagship project has produced a dual
targeted kinase inhibitor for treatment of rare
cancers (Pz-1). Although there are several
clinically utilized multi-kinase inhibitors, their
activity profiles are not optimized, resulting in
unintended off-target effects. We have
identified the first balanced dual inhibitor,
strategically engineered to both starve and kill
malignant tumor growth.
Compared to traditional drug discovery, rational drug design aims to develop small
molecules capable of interacting with a specific target to achieve precise, therapeutic
effects. Our lab designs and synthesizes novel compounds that inhibit well-established and
emerging drug targets for the treatment of multiple disease states. By employing rational
drug design techniques, we are able to quickly identify hits for targets of interest and
optimize compounds for further development.
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Single Agent Polypharmacology
Novel Synthetic Methodologies
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Current Project Paradigms
Rational Drug Design
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Professor Hong-yu Li is an ex-pharma researcher, having
spent 10+ years at Eli Lilly and Company as a team leader in
medical chemistry. Professor Li has discovered two drugs
that are in Phase II clinical trials and has started two
companies from academic research programs. He brings
this expertise to the laboratory everyday, identifying areas
of medicine with un-met medical needs that could benefit
from therapeutic development. As a graduate student in
Professor Li’s laboratory, you will become well versed in
translational medicinal chemistry. Specifically, you will gain
immense experience in drug design, drug synthesis, and in
vitro assay development and analysis. You will further
expand your knowledge base to include in vivo study design,
execution, and analysis ranging from orthotopic models of
disease
to
determining
pharmacokinetic
and
pharmacodynamic drug
properties. The research in
Professor Li’s lab covers various disease disciplines including
oncology, CNS, endocrinology, and immunology.
Expanding Therapeutic Diversity
Therapeutic Discovery Strategies
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Biotage Initiator Microwave Synthesizer
LabChip® EZ Reader II
World-Renowned Collaborators
National Collaborators
Neil P. Shah, MD/PhD: University of California, San Francisco, CA
John Kuriyan, PhD: Howard Hughes Investigator, University of California, Berkeley, CA
Ning Zheng, PhD: Howard Hughes Investigator, University of Washington, Seattle, WA
Shuxiang Zhang, PhD: MD Anderson Cancer Center, Houston, TX
Wael El-Rifai, MD/PhD: Vanderbilt University Medical Center, Nashville, TN
Monica Guzman, PhD: Weill Cornell Medical College, Cornell University, New York, NY
Haiyong Han, PhD: Translational Genomics Research Institute, Phoenix, AZ
Hui-Kuan Lin, PhD: Wake Forest School of Medicine, Winston-Salem, NC
Ichiro Nakano, MD/PhD: University of Alabama, Birmingham, AL
5
s
PMT-254 was discovered in Professor Li’s
laboratory from a student's thesis and
was funded for an R01 ($1.5 million) The
compound is also under late-stage preclinical development and was awarded a
small business grant for $300k.
www.synactixpharma.com
International Collaborators
Massimo Santoro, MD/PhD: Università di Napoli Federico II, Italy
Neil McDonald, PhD: The Francis Crick Institute, United Kingdom
Stefan Knapp, PhD: Goethe University Frankfurt, Germany
Wenhao Hu, PhD: East China Normal University, China