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Wednesday, June 19

7:30 am Morning Coffee

8:25 Chairperson’s Remarks

Doriano Fabbro, Ph.D., CSO, Piqur Therapeutics


» 8:30 Keynote Presentation

Kinase Inhibitors: Lessons Learned?

Doriano Fabbro, Ph.D., CSO, Piqur Therapeutics

Our knowledge on the structural determinants of kinase inhibition by small molecules binding to the ATP pocket has advanced steadily in the past years. We will give an overview on the status quo of kinase inhibition and discuss an example on how protein kinases can be structurally affected by selective kinase inhibitors. In addition we will also discuss on how to target kinases whose cellular signaling pathways are only poorly understood. 

Screening and Validation 

9:00 Evaluation of the PI4KIIIα Lipid Kinase as a Hepatitis C Virus Drug Target: From Inhibitor Screening to Animal Models

Frederic Vaillancourt, Ph.D., former Senior Research Scientist, Department of Biological Sciences, Research and Development, Boehringer Ingelheim (Canada) Ltd.

PI4KIII is an essential host cell factor for HCV replication. Screening, using an in vitro biochemical lipid kinase assay, led to the identification of potent inhibitors. In cell culture studies these inhibitors were used to demonstrate that the kinase activity was essential for HCV RNA replication, and a resistance study performed, using two of these inhibitors, provided additional insight into the potential role of PI4KIIIα and its product in the HCV viral life cycle. A comprehensive assessment of PI4KIIIα as a drug target in vivo through conditional transgenic murine lines that mimic target-specific inhibition in adult mice demonstrated an essential host physiologic role for PI4KIIIα.

9:30 Coffee Break

10:00 Fitting Technology to Screening Strategy: A Probe Displacement Assay to Help Identify Novel Protein Kinase Inhibitors

Ramesh Padmanabha, Ph.D., Principal Scientist, Lead Discovery, Lead Profiling and Compound Management, Bristol-Myers Squibb R&D

The talk will outline assay design process to select the probe displacement assay over standard kinase activity assays. The details of the HTS will also be discussed and will include validation, quality control, and data analysis. The outcome from the screen and selectivity data will also be presented.

10:30 Accuracy of Docking and Scoring Into Kinases

Istvan Enyedy, Ph.D., Senior Scientist, Small Molecule Drug Discovery, Biogen Idec

Scoring functions cannot predict binding affinity and it is challenging even to distinguish between compounds that differ by more than 100 fold in potency. The talk will evaluate the influence of structure and constraints on the outcome of docking and scoring of compounds into 10 kinases and more than 100 structures. In addition, a comparison of several metrics in estimating the precision of scoring will be presented.


Structure - Based Design  

11:00 Structure-Based Drug Design: Redefining Protein-Ligand Interactions

Jose Duca, Ph.D., Head, Computer-Aided Drug Discovery, Novartis

Since the introduction of the lock and key hypothesis,structure-based drug design has been equivalent to understanding and designing protein-ligand interactions. A novel theory of binding that encompasses protein-ligand interactions will be introduced and exemplified.

11:30 Enjoy Lunch on Your Own

1:15 pm Chairperson’s Remarks

Adam C. Palmer, Ph.D., Postdoctoral Fellow, Department of Systems Biology, Harvard Medical School

(1) the special role that structure-based drug design can play in treating drug resistant infectious diseases
(2) how considering the evolution of resistance during drug development could produce drugs with more long-lasting clinical efficacy
(3) how drug resistance can be used as a tool to understand mechanism of drug action

1:20 Structure-Based Design of Potent and Selective Inhibitors of PI3-Kinase Delta

Jeremy M. Murray, Ph.D., Scientist, Structural Biology, Genentech

Inhibition of PI3Kδ is considered to be an attractive mechanism for the treatment of inflammatory diseases and leukocyte malignancies. Using a structure-based design approach, we have identified a series of potent and selective inhibitors of PI3Kδ. These inhibitors do not occupy the induced selectivity pocket between Trp760 and Met752 that is observed for other families of selective PI3Kδ inhibitors. Instead, the selectivity of the compounds for inhibition of PI3Kδ relative to other PI3K isoforms appears to be due primarily to the strong interactions these inhibitors are able to make with Trp760 in the PI3Kδ binding pocket. This talk will discuss the structural understanding of the selectivity of these inhibitors against other isoforms, pharmacokinetic properties and the ability of select compounds to inhibit the function of B-cells in vivo.

1:50 MD Simulations of Mutant and WT PI3Kα: Insights into the Mechanism of Overactivation and Implications for Drug Design

Zoe Cournia, Ph.D., Investigator, Biomedical Research Foundation, Academy of Athens

Understanding how the p110α H1047R mutation causes tumorigenesis is central to developing new therapeutics for cancer. To this end, MD simulations in aqueous solution were carried out for 100 ns for both WT and mutant proteins. Our results indicate that key regions of the protein, such as the catalytic, activation, membrane binding loops and the C-terminus, all exhibit significantly different dynamics in the mutant with respect to the WT protein.

2:20 Guiding the Design of Robust Inhibitors Targeting HIV and HCV Proteases by Using the Dynamic Substrate Envelope

Aysegul Ozen, Ph.D. Candidate, Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School

Drug resistance is a major concern in the treatment of quickly evolving diseases. At the molecular level, drug resistance reflects a subtle change in the balance of molecular recognition by the target enzyme due to mutations in favor of substrate processing versus inhibitor binding. Robust inhibitors can be designed by mimicking the binding features of the natural substrates to minimize the chances of resistance.

2:50 Refreshment Break in the Exhibit Hall with Poster Viewing

Drug Resistance

3:30 Towards a New Generation of Antimicrobial Antifolates

Dennis L. Wright, Ph.D., Professor of Pharmaceutical Sciences and Chemistry, University of Connecticut

We are using a structure-based design approach to develop potent and selective inhibitors of the enzyme dihydrofolate reductase (DHFR) from a variety of pathogenic organisms. Analysis of crystal structures of trimethoprim-resistant and naturally insensitive enzymes led to the design of a series of propargyl-linked antifolates characterized by high potency, good selectivity over the human form of the enzyme and good anti-microbial activity.

4:00 Understanding Drug Mechanism of Action by Target Gene Overexpression

Adam C. Palmer, Ph.D., Postdoctoral Fellow, Department of Systems Biology, Harvard Medical School

The molecular targets of drugs can sometimes, but not always, be identified amongst genes that confer drug resistance when overexpressed. We quantitatively overexpressed genes encoding known antibiotic targets and observed that drug resistance does not only increase; it can remain unchanged, decrease, or even have a non-monotonic dependence on target expression. These diverse effects are explained by simple models considering gene toxicity and drug-induction of harmful target-catalyzed reactions. The relation between drug resistance and target expression may reveal unexpectedly complex mechanisms of drug action.

4:30 Close of Conference

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