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

RISE Honors Seminar 2015 Ronald Doll RISE Dept. S-332 X 3168 rdoll@drew.edu 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

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

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

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

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)

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

Boyden chamber used to measure in vitro membrane transport

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

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

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