Cambridge Healthtech Institute’s Inaugural

Lead Optimization for Drug Metabolism and Safety

Tools and Strategies for Incorporating Safety into Drug Design

April 6, 2018 | Hilton Bayfront | San Diego, California

The more chemists know about how the structure of a compound can possibly impact its drug-like properties, the faster they can optimize it for drug development. Lead compounds in drug discovery need to be optimized for both efficacy and safety. Unfortunately, some of the adverse events related to the compound do not surface until much later in development. This unique one-day symposium on Lead Optimization for Drug Metabolism and Safety will bring together experts from DMPK, safety pharmacology and toxicity groups to talk about some of the factors that must be considered early in lead optimization, particularly for addressing safety concerns. The symposium will introduce chemists to some key concepts in biotransformation, drug metabolism, drug transport, and drug clearance using relevant case studies and research findings, which will hopefully help them design and develop better drug candidates.


Final Agenda

Friday, April 6

7:25 am Registration and Morning Coffee


7:55 Welcome and Opening Remarks

Tanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute

John C. L. Erve, PhD, DABT, Consultant, Jerve Scientific Consulting, Inc.

8:00 FEATURED PRESENTATION: Addressing Biotransformation Issues in Early Discovery

Deepak Dalvie, PhD, Senior Director, DMPK, Celgene

Drug metabolism plays an important role in the discovery and development of a drug candidate. Addressing metabolism issues early on can result in candidates with less metabolism as well as bioactivation liabilities. Strategies and examples of role of metabolism in early discovery will be discussed in this talk.

8:30 Principles of Metabolite Identification by Mass Spectrometry for Drug Discovery and Development

John_Erve_2John C. L. Erve, PhD, DABT, Consultant, Jerve Scientific Consulting, Inc.

Metabolite identification (Met ID) studies are an important component for both drug discovery and drug development efforts. Mass spectrometry, particularly high mass accuracy techniques, is the primary tool for Met ID studies. Chemists often rely on internal or external scientists to perform metabolite identification and characterization but will benefit by understanding how it is done. This talk will cover strategies used to identify drug metabolites allowing chemists to better understand the strengths and limitations of these studies.

9:00 Coffee Break


9:30 Detection and Assessment of Reactive Drug Metabolites in Drug-Mediated Hepatotoxicity

Mark_GrilloMark Grillo, PhD, Staff Scientist, Drug Metabolism & Pharmacokinetics, MyoKardia, Inc.

A number of toxic drugs undergo bioactivation to chemically-reactive metabolites that bind covalently to endogenous macromolecules, proteins, DNA leading to organ toxicity and carcinogenesis. Current experimental techniques used to detect and assess the potential liabilities of reactive metabolites and how information from mechanistic in vitro studies can be employed to redesign candidate drugs leading to blocked or minimized bioactivation and decreased toxification will be discussed.

10:00 Application of Drug Transporters in Drug Discovery

Caroline Lee, PhD, Consultant, DMPK Solutions Inc.

Transporters play a key role in the disposition of drugs. Transporters contribute to drug efficacy, drug interactions and may limit desired drug exposure. The rationale and identification of the transporters to implement in drug discovery will be discussed as well as the difficulties that may be encountered in translating in vitro data to clinical outcome.

10:30 Addressing the Challenges of Low Clearance and Intracellular Free Drug Concentration

Li_DiLi Di, PhD, Research Fellow, Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc.

Low clearance compounds continue to increase in drug discovery and lack of low clearance tools can lead to over-prediction of clearance, dose and under-prediction of half-life. Intracellular free drug concentration is most relevant for development of PK/PD relationships and prediction of drug-drug interactions. This presentation will discuss approaches to address these challenges and their applications in drug discovery.

Cyclica11:00 Elucidating Mechanism-of-Toxicity of FAAH Inhibitors via Proteome-Screening

Mackinnon StephenStephen MacKinnon, PhD, Director, Research and Development, Cyclica Inc..

Cyclica has developed a protein structure-based and AI-augmented drug discovery platform (Ligand Express) that provides a unique panoramic view of small-molecules in development, by identifying on-/off-targets that may be expected as well as those that are unanticipated. Accordingly, Ligand Express can augment R&D programs by elucidating MoA of small molecules.

11:15 Enjoy Lunch on Your Own

12:00 pm Session Break


1:00 Chairperson’s Remarks

Mark_GrilloMark Grillo, PhD, Staff Scientist, Drug Metabolism & Pharmacokinetics, MyoKardia, Inc.

1:05 Use of Integrated DMPK Approaches to Facilitate Design of Brain Penetrant Kinase Inhibitors

Xingrong Liu, PhD, Principal Scientist, Drug Metabolism and Pharmacokinetics, Genentech, Inc.

1:35 A Proposed ADME Optimization Workflow for Covalent Inhibitors

Mehran_MoghaddamMehran Moghaddam, PhD, MBA, Founder and CEO, OROX Biosciences

With the renewed interest in covalent inhibitors comes the responsibility to advance only compounds with drug-like properties in discovery programs. The traditional small molecule reversible drug discovery workflow includes target identification and validation, lead identification, lead optimization and profiling and optimizing for ADME properties are paramount in obtaining acceptable efficacy and safety. This presentation will contrast the ADME workflow for discovery of covalent verses reversible inhibitors.

2:05 Predicting Human PK and Exposure in Discovery to Inform Lead Optimization and Candidate Selection

Natalie Hosea, PhD, DMPK San Diego Site Head, Takeda

Prediction of human pharmacokinetics and drug-related exposure underpins early decision-making in drug discovery. More specifically, early human predictions enable identification of key liabilities for focused optimization strategies as well as enabling assessment of early safety information when coupled with pharmacology information. In this section, case studies on the application of predictions to optimization strategies and compound advancement will be discussed.

2:35 Co-Presentation: Strategies and Application of CYP Inhibition and Phenotyping Assays to Optimize SYK Inhibitor Drug-Drug Interaction Risk Profiles

David_StresserDavid M. Stresser, PhD, Principal Research Scientist, AbbVie, Inc.

Michael Hoemann, PhD, Senior Scientist, Department of Chemistry, AbbVie, Inc.

Cytochrome P450 interaction liabilities receive higher scrutiny in therapeutic areas requiring low tolerance for drug-drug interactions. In these competitive market areas, rapid access to robust CYP metabolism and inhibition data is crucial to a program’s success. We will review early ‘perpetrator’ and ‘victim’ assays and how they were used at AbbVie to successfully address a significant FmCYP3A4 and time-dependent inhibition liability in a Spleen Tyrosine Kinase (SYK) program.

3:05 Refreshment Break


3:35 Kriging - A New Approach for Building ADMET Prediction Models

Istvan_EnyedyIstvan Enyedy, PhD, Principal Scientist, Medicinal Chemistry, Biogen

Kriging is using the correlation of the distance between molecules with the difference between their activity/ADMET properties for in silico predictions. We have considered this algorithm since it allows us to easily build, evaluate, and maintain models and has a report format that allows users to judge the accuracy of the predictions. The performance of eighteen models and how training sets impact it will be presented.

4:05 Sensitive in vitro Screening for Structure/Tissue Toxicity Assessment with Rapid-Turnaround Time

Ian_SweetIan Sweet, PhD, Associate Professor, Department of Medicine, University of Washington

I will present sensitive technology we have developed that continuously measures time courses of pharmacologically relevant drug effects on solid tissue samples. The accuracy and throughput is well suited to quantify and rank effects and toxicity of drug metabolites, chemical libraries and lead candidates. Data generated will be useful for the analysis of drug effects on human vs. animal tissue, target organs and drug-drug interactions.

4:35 In vitro Tools for Successful Prediction of Human Hepatic Clearance

Jasleen_SodhiJasleen Sodhi, Graduate Student, Laboratory of Dr. Leslie Benet, Pharmaceutical Sciences and Pharmacogenomics Program, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco

Accurate prediction of human pharmacokinetic properties is critically important in drug discovery. Of particular importance is the prediction of hepatic clearance, which largely determines drug exposure and contributes to projections of dose, drug half-life and bioavailability. This talk will cover common in vitro techniques used to predict hepatic clearance of new chemical entities and the fundamentals of in vitro to in vivo extrapolation (IVIVE) of drug clearance.

5:05 End of Conference