Cambridge Healthtech Institute’s 4th Annual

Biophysical Approaches for Drug Discovery

New Methods and Lead Generation Strategies for Medicinal Chemists

April 12, 2019

 

Recent advances in automation and sensitivity of biophysical approaches for measuring biomolecules interacting with one another has spurred progress in drug discovery. Technologies such as nuclear magnetic resonance (NMR), surface plasmon resonance (SPR), other biosensor-based assays, isothermal titration calorimetry (ITC), and thermal shift assays (TSAs) have enabled discovery of compounds targeting protein-protein interactions and complex membrane protein targets. These target classes are more difficult to ‘drug’ because they are either harder to solubilize or not as amenable as are traditional intracellular enzyme targets to in-vitro-based, biochemical functional assays for high throughput screening. Fragment-based drug design is also another lead generation approach that is very dependent on biophysical technologies. Cambridge Healthtech Institute's 4th Annual Biophysical Approaches for Drug Discovery symposium will bring together medicinal chemists, structural biologists, biophysical chemists and computational researchers to discuss the latest biophysical advances and see examples and discuss strategies for when to apply them for more efficient drug lead generation.


Final Agenda

Friday, April 12

7:30 am Registration Open and Morning Coffee

INTEGRATING BIOPHYSICAL APPROACHES

7:55 Welcome and Opening Remarks

Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute

Seungil Han, PhD, Associate Research Fellow, Structure Biology & Biophysics, Pfizer Global R&D

8:00 FEATURED PRESENTATION: Characterization of Novel STING Ligands Using SPR and Orthogonal Approaches

Gottfried Schroeder, PhD, Senior Scientist, Department of Pharmacology, Merck Research Labs - Boston


8:30 Advanced Biophysical Methods for Driving Lead Generation in the Right Direction

Mela Mulvihill, PhD, Scientist, Biochemical & Cellular Pharmacology, Genentech

Difficult to drug targets require advanced biophysical methods for hit identification, characterization, and optimization through the early discovery hit-to-lead phase. Using case studies, I will present our advanced toolkit of novel mass spectrometry and label-free biophysical assays used for screening, establishing mechanism of action, and kinetic measurements for compound optimization. The on-going projects I present will include a class of compounds that induce target degradation referred to as Chemical Inducers of Degradation (CIDEs).

9:00 Networking Coffee Break

INNOVATIONS IN BIOPHYSICAL APPROACHES

9:30 NMR Molecular Replacement: A Method to Probe Protein-Ligand Complexes in the Absence of Crystal Structures

Julien Orts, PhD, Professor, Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH

I will describe our novel NMR2 (NMR Molecular Replacement) method which we believe provides an avenue for the fast and robust determination of atomic resolution binding pocket structure of ligand-protein complexes when obtaining well-diffracting crystals is difficult. It is quicker than the current x-ray crystallography alternative of liquid-state NMR. I will present multiple NMR2 applications covering several ligand topologies ranging from peptidomimetic to small molecules that bind strongly or weakly to protein receptors.

10:00 Engaging Kinases in Living Cells: Probing Drug-Target Interactions with Chemical Biology and Biophysical Tools

Jordan Carelli, PhD, Senior Scientist, Oncology RU, Pfizer

10:30 Studying Small Molecule-Membrane Protein Binding Kinetics Using Virion Oscillators

Guangzhong Ma, Graduate Student, Chemistry, Laboratory of N. Tao, Arizona State University

Our ‘membrane protein binding kinetics’ method measures binding induced charge change. We apply an alternating electric field to oscillate virions with GPCRs expressed on the surface and measure oscillation amplitude of the virions with sub-nm precision. The binding of small molecule changes the charge on the virion surface and thus changes the oscillation amplitude. By tracking the oscillation amplitude in real-time, the binding kinetics can be obtained.

11:00 Sponsored Presentation (Opportunity Available)

11:15 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:00 pm Session Break

CRYO ELECTRON-MICROSCOPY

1:00 Chairperson’s Remarks

Mela Mulvihill, PhD, Scientist, Biochemical & Cellular Pharmacology, Genentech

1:05 CryoEM Applied to Drug Discovery

Seungil Han, PhD, Associate Research Fellow, Structure Biology & Biophysics, Pfizer Global R&D

1:35 Using Cryo-Electron Microscopy to Explore Endosomal GPCR Signaling

Alex Thomsen, PhD, Assistant Professor, Department of Surgery, Columbia University

We are applying a variety of electron microscopy (EM) and computational methods to obtain high-resolution structural information about the megaplex of a single GPCR that interacts simultaneously with β-arrestin and G protein, and to visualize GPCR signaling on the endosomal surface within living cells.

2:05 Sponsored Presentation (Opportunity Available)

2:35 Networking Refreshment Break

DRUG DISCOVERY APPLICATIONS

3:05 The Critical Role of Biophysical Methods (with a Focus on SPR) in Advancing CDK7 Drug Discovery

Kristin Hamman, MS, Research Investigator, Biochemistry, Syros Pharmaceuticals

Small molecule inhibition of CDK7 has been shown to have anti-proliferative effects on cancer cell lines and antitumor activity in mouse models. We have established methods to measure time-dependent inhibition of CDK7 by covalent compounds, which contributed to selection of a clinical candidate, SY-1365, currently in Phase I trials.

3:35 Structural and Functional Characterization of Phospholipases as a Target for ALS

Jay Chodaparambil, PhD, Research Scientist, Chemical and Molecular Therapeutics, Biogen, Inc.

4:05 NMR and Enthalpy Screening of Combinatorial Libraries to Ligand Discovery

Maurizio Pellecchia, PhD, Professor of Biomedical sciences, UC Riverside, School of Medicine, Riverside, CA

We have recently proposed novel evolution-based ligand discovery approaches, in which the principles of positional scanning combinatorial chemistry and fragment-based drug design are combined with biophysical screening techniques, including NMR- and enthalpy- based strategies, to identify novel ligands from large collections of compounds (105-106 or larger). I will reiterate the basic principles of the approaches and report several recent applications including tackling challenging drug targets.

4:35 Close of Conference

* The program is subject to change without notice, due to unforeseen reason.