1. Can Drug Discovery Research be Done At An Undergraduate Institution?
Yes!
Some Details of the Preclinical Drug Discovery Process
Done at Drew University

2. RISE Honors Seminar 2015 Ronald Doll RISE Dept. S-332 X 3168
Training – Synthetic Organic Chemist (Ph.D. Duke Univ.)
Organic chemistry is the chemistry or carbon containing compounds
Career – Industrial Drug Discovery for 34 years
Medicinal Chemist, Schering-Plough/Merck (Oncology Drug Discovery)
RISE (2010) – Drug Discovery Projects
Interests: Anything to do with molecules. Astronomy and Molecular
Nano-electronics

3. Preclinical Drug Discovery at Drew
Target
Selection
Target
Validation
Assay
Development
Hits
& Leads
&
Lead
Optimization
Screening
Medicinal Chemistry activities in my lab
Activities of Medicinal Chemistry
Identify “hit compounds” (have desired biological activity)
Identify “lead compounds” for medicinal chemistry to work on (could lead to a drug)
Optimize the lead compounds, by following an SAR, to identify a “Development Candidate”
Development candidate must have good:
Potency
Selectivity
“Drug Like Properties”
Chemical stability and crystallinity
The ability to cross biological membranes – compound needs to get into tissue
Metabolic stability – must have a workable lifetime in humans
Efficacy and safety in animal models

4. The Cell, Signal Transduction and Cancer
From
p53 is known as “Protector of the Genome”
p53 stimulates the production of cell-control proteins

5. Mutant p53 in human tumor cells is a good target
Done in collaboration with Dr. DasMahapatra
Discover and develop compounds that reactivate mutant p53 in human tumor cells
p53 is a transcription factor for cell control proteins
p53 is a tumor suppressor agent
p53 is mutated in about 50% of all human tumors
DNA Damage
Oncogene Activation
Activate p53
Activated p53 binds to DNA and allows genes to produce proteins (transcription factor)
Cell Growth Arrest
p21
Apoptosis
Senescence
Bax
Angiogenesis
Inhibition
Maspin
DNA Repair
ST13

6. Identify hit structures and develop them into lead structures
Reported to bind to p53
Reported to inhibit MetAP-2 protease which
inhibits angiogenesis
We showed that compounds in both classes reactivate mutant p53 in human tumor cells
making them lead structures
We have synthesized over 70 analogues to optimize:
Potency (Dr. Das lab)
Selectivity (Dr. Das lab)
Drug-like properties (My lab)

7. Determine if our compounds cross biological membranes
Biological membranes that compound must cross
Cell membrane – compound must get into cell to reactivate mutant p53
GI tract membrane – for oral activity
Blood Brain Barrier (BBB) – for activity in the CNS
A Boyden chamber is used to measure in vitro membrane transport of our
compounds
LC/MS is used to quantify the amount of compound transported across the
membrane
Done by Randa Barsoom and Godfrey Osawe

8. Boyden chamber used to measure in vitro membrane transport

9. Determine if our compounds resist human metabolism (in vitro)
Compounds that enter our body are metabolized in the liver by cytochrome P-450
enzymes (CYP450).
This converts the compounds to polar water soluble compounds that can be excreted.
Our procedure
We incubate our compounds in buffer with human liver microsomes and NADPH
We follow the metabolism of our compounds over time and analyze by LC/MS
Metabolites will have MW + 16, 32, 64 etc. of the parent molecule.
Done by Megan McAleavy and Josh Hsu

11. Previous Students’ Research Topics
DNA damaging agents as an approach to anti-cancer therapy
Immunological approaches to treating cancer
Gene therapy approaches to drug discovery
Could Alzheimer's disease be communicable?
The role of aflatoxin in food, causing cancer
Kinase inhibitors as potential therapy for Alzheimer’s disease

12. Possible Research Projects
Any scientific topic
Anything related to the causes and treatment of diseases
Any topic that involves molecules