RISE Honors Seminar 2014 Ronald Doll RISE Dept. S-332 X 3168 Training – Synthetic Organic Chemist (Ph.D. Duke Univ.) - National Institute of Health Postdoctoral Fellow (Columbia Univ.) Organic chemistry is the chemistry or carbon containing compounds Career – Industrial Drug Discovery for 34 years Medicinal Chemist, Schering-Plough/Merck (Mostly Oncology Drug Discovery) RISE (2010) – Continuing Drug Discovery in Oncology and CNS

Some Drugs Developed by my Group At Schering-Plough and Merck Mostly in Oncology Spirapril, angiotensin-I converting inhibitor An anti-high blood pressure medication Lonafarnib, farnesyl transferase inhibitor Designed as anti-tumor agent, now used to treat Progeria Dinaciclib, Cyclin-dependent kinase inhibitor An anti-tumor agent in Phase II clinical trial for lung cancer

Some Drugs Developed by my Group At Schering-Plough and Merck MK-8242, HDM2 inhibitor (HDM2 degrades p53) An anti-tumor agent in Phase I clinical trial for solid tumors MK-8353, ERK kinase inhibitor An anti-tumor agent in Phase I clinical trial for solid tumors (melanoma)

Our Drug Discovery Efforts at Drew University Cancer – uncontrolled replicating cells that can invade and colonize other sites in the body Oncology - In collaboration with Dr. Bimal DasMahapatra, a biology RISE Fellow p53 and mGluR4 project teams 2015

From The Cell, Signal Transduction and Cancer Cancer is HUNDREDS of diseases driven by different mutations p53

Anti-cancer Drug Discovery Approaches Early approach - Chemotherapy Develop compounds that prevent cell replication or kill replicating cells Issue – Normal replicating cells, immune cells, are also killed causing toxicity Recent approach – Targetet directed therapy (Oncogenes) Identify and inhibit the mutated or over-activated proteins causing the cancer Gleevec inhibits the bcr-abl oncoprotein driving CML, a form of leukemia. Immunotherapy also falls in this category Issues – A cancer can be driven by several oncoproteins. Inhibiting one of these proteins may not be enough The genetic makeup of cancer cells can change leading to resistance Surgery and radiation

Our Approach to Preclinical Drug Discovery 1.Identify a biological target (whole animal, cells, proteins) responsible for the disease 2.Develop assays for the biological target 3.Identify lead chemical structures as starting points 4.Develop a drug candidate from the leads. Change compound structures to optimize: Potency – Requires small amount of compound to get desired effect Selectivity – Few off-target side effects (low toxicity) Drug-like properties The ability of the compound to cross biological membranes, GI track and BBB The ability of the compounds to resist human metabolism 5. In vivo (whole animal) efficacy and toxicity evaluation This is our current drug discovery process at Drew

Identify a biological target – p53 (with Dr. DasMahapatra’s Group) DNA DamageOncogene Activation Activate p53 Activated p53 binds to DNA and allows genes to produce proteins (transcription factor) Cell Growth Arrest p21 Angiogenesis Inhibition Maspin DNA Repair ST13 Apoptosis Senescence Bax MDM2 Degrades p53 p53 is called “The Guardian of the Genome” It is the main cell-control “gate keeper” p53 is mutated in 50% of all human cancers Mutant p53 has an incorrect conformation (shape) Mutant p53 is inactive as a transcription factor and can also act as an oncoprotein Can we identify compounds that correct the conformation of mutant p53?

Develop assays for the biological target –Dr. DasMahapatra’s group Determine the potency of our compounds on human colon and brain cancer cells Does a compound reactivate mutant p53 in human tumor cells? At what concentration does a compound kill human tumor cells? Determine the selectivity of our compounds At what concentration does a compounds kill tumor cells? At what concentration does a compounds kill non-p53 (normal) cells? This ratio determines a therapeutic index Identify lead chemical structures as a starting point The quinoline class Shown to inhibit angiogenisis 2010 patent The benzimidazole class Shown to bind to p patent

Evaluate the drug like properties of a compound Use an artificial membrane permeation assay and quantitatively assay by LC/MS GI membrane BBB membrane Correlate membrane permeability with logP (compound polarity) Use commercial human liver microsomes (CYP450) and LC/MS to determine: In vitro human metabolic rate and compare with marketed drugs Identify the metabolites so we know how to modify the metabolism Synthesize new compounds to optimize potency, selectivity and drug like properties using structure activity relationships, SAR RD 1 Mut p53 react = yes Viabil DLD1 EC 50 = 1.3 uM Therapeutic index = 4.7 BBBTR = 0 ClogP = 4.3 Intrin. H. CL T 1/2 = 39 min

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 via prions? The role of mold aflatoxin in food, causing cancer Can natural compounds in Aloe Vera be starting points for drug discovery?