Thursday, October 15, 2020 | 1:00 PM 4:00 PM

Thursday, October 22, 2020 | 1:00 PM 4:00 PM

Thursday, October 29, 2020 | 1:00 PM 4:00 PM

Lead Instructor: Terrence P. Kenakin

Terrence P. Kenakin, PhD, Professor, Pharmacology, University of North Carolina at Chapel Hill

Beginning his career as a synthetic chemist, Terry Kenakin received a PhD in Pharmacology at the University of Alberta in Canada. After a postdoctoral fellowship at University College London, UK, he joined Burroughs-Wellcome as an associate scientist for 7 years. From there, he continued working in drug discovery for 25 years first at Glaxo, Inc., then Glaxo Wellcome and finally as a Director at GlaxoSmithKline Research and Development laboratories at Research Triangle Park, North Carolina, USA. Dr. Kenakin is now a professor in the Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill. Currently he is engaged in studies aimed at the optimal design of drug activity assays systems, the discovery and testing of allosteric molecules for therapeutic application, and the quantitative modeling of drug effects. In addition, he is Director of the Pharmacology graduate courses at the UNC School of Medicine. He is a member of numerous editorial boards, as well as Editor-in-Chief of the “Journal of Receptors and Signal Transduction.” He has authored numerous articles and has written 10 books on Pharmacology.

Series Description

This training series addresses how to predict therapeutic activity of drugs being developed against G Protein-Coupled Receptors (GPCRs). Drug candidate profiles from in vitro test systems often do not adequately reflect in vivo responses. We focus on pharmacological procedures needed to convert ‘descriptive data’ (what we see) to ‘predictive data’ (what will be seen) through universal pharmacological scales such as affinity, efficacy, cooperativity parameters, offset rates, etc. The desired outcome is to more fully define GPCR ligand properties that reduce attrition in late-stage drug development. I illustrate how concepts introduced over the past 15 years have considerably expanded and revitalized the possibilities for GPCRs as therapeutic targets.

Who Should Attend

Any medicinal chemist, synthetic chemist, or biologist involved in drug discovery either in industry or academia. In addition, anyone involved in the regulatory, clinical, legal and marketing aspects of the drug discovery and development industry could benefit from an increased understanding of GPCR drug targets and their application to medical therapies.

Part 1: Lead Optimization, GPCR Target Engagement, Validation, Efficacy and Agonism

Drugs interact with living physiology and have different effects in tissues in vivo of differing sensitivities and setpoints. Pharmacology takes the ‘snapshot’ (data from a test assay) and projects the whole ‘movie’ (spectrum of effects in vivo). Comprehensively defining the pharmacology of candidates ensures a better understanding of effects seen in the clinic and better definition of follow up molecules. This effect is especially important for developing agonists. Molecular dynamics and new functional assay systems have revealed that some agonists preferentially activate certain cellular pathways at the expense of others (biased signaling); this offers a new vista for discovery.

Part 1 Topics to be Covered:

• The Lead Optimization Process/‘Fail Early /Fail Fast’ Mentality
• Descriptive vs. Predictive Data/‘Know Your Molecule’: Utilizing pharmacology to fully characterize candidates
• Verisimilitude of Data to Models/Fitting Data to Models for Mode of Action
• Binding vs. Functional Assays/The Impact of Kinetics on Response
• Target choice and validation/pathway validation/determining target engagement: in vitro/in vivo
• Molecular Mechanism of Efficacy
• The ’Quality’ of Efficacy (multiple signaling cascades)
• Efficacy- vs Affinity-dominant Potency
• The Black/Leff Operational Model
• Biased Agonism: Mechanism, Quantification

Part 2: GPCR-Targeted Antagonists: Orthosteric Antagonists, Allosteric Modulators

Drugs that do not directly signal but rather retard the production of physiological signals are antagonists. There are two modes of antagonism: (1) Orthosteric whereby the antagonist binds to the agonist binding site and blocks effect through steric hindrance and (2) Allosteric whereby the agonist and antagonist bind to separate sites on the target and the interaction between them occurs through a conformational change in the protein. In addition, allosteric modulators can be used to rejuvenate failing physiological systems, an area of increasing and active therapeutic research.

Part 2 Topics to be Covered:

• Competitive and non-competitive orthosteric antagonism
• Agonist-antagonist hemi-equilibria (calcium assays)
• Positive efficacy of antagonists: partial agonism
• Negative efficacy of antagonists: inverse agonism
• Allosteric modulation/unique properties of modulators
• Allosteric binding models (hall model)
• Functional allostery: NAMs as antagonists
• Allosteric agonists
• Positive allosteric modulators (PAMs)
• Translation of allosterism

Part 3: GPCR Ligand Development: Pharmacokinetics and Early Safety Studies

All drug candidates meet the common bottleneck of needing to enter the body, distribute to the appropriate therapeutically relevant organ, stay there long enough to cause beneficial effect and cause no harm. In 1991, 48% of all new candidate molecules failed because of inadequate Pharmacokinetics (PK); this number has fallen to <1% at present time largely because of the large number of rapid, predictive and inexpensive ADME tests now available (we have no excuse losing a molecule due to PK). This module discusses these tests along with chemical strategies to modify PK properties. In addition, critical early safety studies will be included.

Part 3 Topics to be Covered:

• General principles of pharmacokinetics
• Absorption/distribution
• Hepatic metabolism (in vitro assays, prediction of hepatic clearance)
• Renal clearance
• Multiple dosing to achieve steady-state plasma levels
• In vivo PK; Linear and non-linear PK
• Definition of toxicity (dose-dependent vs. idiosynchratic)
• Basic early toxicity tests (cytotoxicity, hERG, mutagenicity)