Cambridge Healthtech Institute’s 3rd Annual

GPCRs & Membrane Proteins

Designing Drugs Targeted at Proteins with Multiple Membrane-Spanning Domains

April 10-11, 2019

Cell surface complex membrane proteins such as G protein-coupled receptors (GPCRs), ion channels and transporters are attractive targets to design or discover drug agents against. They play important physiological roles and are accessible to compounds circulating in the body, including potential new drug agents. However, due to their membrane-embedded nature, this drug target class is less tractable to structure-based drug design approaches that rely on solubilization of the proteins to obtain X-ray crystal structures. However, genetic ‘tricks’ that facilitate solubilization, better biophysical tools that enable study of proteins while still in the membrane and advances in electron microscopy are speeding progress in rational drug design and screening efforts against complex membrane proteins. At Cambridge Healthtech Institute's 3rd Annual GPCRs & Membrane Proteins conference, join fellow medicinal chemists, structural biologists, biophysical chemists and translational researchers to witness and discuss the impact of new structural knowledge about and tools for studying GPCRs and other complex membrane proteins for target-based drug design.

Final Agenda

Wednesday, April 10

12:30 pm Registration Open (20 C/D Foyer) 

12:45 Dessert Break in the Exhibit Hall with Poster Viewing

STRUCTURAL ADVANCES FOR MEMBRANE PROTEINS
31 B/C

1:30 Welcome Remarks

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

1:35 Chairperson’s Opening Remarks

Vsevolod 'Seva' Katritch, PhD, Assistant Professor, The Bridge Institute, University of Southern California

1:40 Structure-Based Ligand Discovery for Class 'A' GPCRs: New Targets and Approaches

Vsevolod 'Seva' Katritch, PhD, Assistant Professor, The Bridge Institute, University of Southern California

With the rapid accumulation of high-resolution crystallographic and cryo-EM data for GPCRs, structure-based virtual ligand screening and rational design are quickly finding their prominent place as mainstream lead discovery and optimization tools. This talk will discuss several recently emerged structural targets for pain, addiction and immune disorders, as well as updates in virtual screening approaches we use to discover new chemotypes as probe compounds for these targets.

2:10 Nanobody-Stabilized Kappa Opioid Receptor Structure and Implications for Biased Opioid Ligand Design

Tao Che, PhD, Postdoctoral Fellow, Bryan Roth Lab, Department of Pharmacology, University of North Carolina Chapel Hill

This presentation will cover the design of biased ligands at the kappa-opoioid receptor (KOR) using the crystal structure of KOR as a model.

2:40 NEW: CXC Chemokine Receptor 4: Structural Updates on a Druggable Target

Tony Ngo, PhD, Postdoctoral Fellow, Kufareva Lab, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego

As a key driver of cancer cell migration and metastasis, the CXC chemokine receptor 4 is a target of several drug development programs. CXCR4 shares an endogenous chemokine CXCL12 with the atypical, intrinsically biased receptor ACKR3, but the structural principles of chemokine binding and receptor activation remain unknown. Our work reveals the basis for CXCL12 interaction and activation of CXCR4, and comparison with ACKR3, with potential implications for drug design.

3:10 Novel Kv7 Ion Channel Openers for the Treatment of Epilepsy

Takeshi Yura, PhD, Vice President, Medicinal Chemistry, Jubilant Biosys Ltd.

Neuronal voltage-gated potassium channels, Kv7s, are the molecular mediators of the M current and regulate membrane excitability in the central and peripheral neuronal systems.  The identification of two distinct chemical series and their optimization towards novel small molecule Kv7 openers will be described.  The results of in vitro and in vivo studies for selected compounds from these series will be presented, including data indicating their efficacy in seizure models.

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Single-molecule FRET analysis of Ligand Efficacy in β2 Adrenergic Receptor - G Protein Activation

Matthieu Masureel, Ph.D., Postdoctoral Scholar, Kobilka Lab, Molecular and Cellular Physiology, Stanford University School of Medicine

I will discuss single-molecule FRET analysis of ligand efficacy in β2 adrenergic receptor - G protein activation. I will also briefly describe the application of this technology to membrane proteins in general. 

5:00 First-in-Class Small Molecule Modulators of Adhesion GPCRs

Gregory Tall, PhD, Associate Professor, Pharmacology, University of Michigan

Adhesion GPCRs control many aspects of developmental transitions, tissue maintenance in adults, and a slew of regulatory functions in various tissues. There is a paucity of small molecule ligands to manipulate the receptor subclass. We recently demonstrated that adhesion GPCRs are activated by a tethered-peptide-agonist mechanism. With this understanding, we engineered receptors for high throughput screening of chemical libraries. We found the first adhesion GPCR small molecule antagonist and the first small molecule partial agonist.

5:30 Breakout Discussions - View All Breakouts

6:15 Close of Day

6:30 Dinner Short Courses*

*Premium or separate registration required.

Thursday, April 11

8:00 am Morning Coffee

8:45 Plenary Session Remarks from Event Director

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

8:50 Plenary Keynote Introduction

Timothy Craig, PhD, HarkerBio

8:55 Plenary Keynote: New Ways of Targeting K-Ras

Frank McCormick, PhD, Professor, HDF Comprehensive Cancer Center, University of California San Francisco

Efforts to find drugs that bind K‐Ras directly have increased recently, enabled by NMR‐based fragment screening, di-sulfide tethering, in silico drug design and biophysical methods such as Second Harmonic Generation (SHG). We will report progress on attacking two sites in the K‐Ras protein; cysteine‐185 (the site of prenylation), and histidine‐95, a residue unique to K‐Ras, to develop covalent K‐Ras inhibitors, as well as compounds identified by SHG and other methods.

9:45 Coffee Break in the Exhibit Hall with Poster Viewing

TRANSPORTERS AND ION CHANNELS

10:40 Chairperson’s Remarks

Matthew Eddy, PhD, Assistant Professor, Chemistry, University of Florida

10:45 A New Era in Discovery of Solute Carrier (SLC) Transporter Modulators

Alan D. Wickenden, PhD, Scientific Director, Discovery Sciences, Janssen R&D

SLC transporters constitute the second largest family of membrane proteins in the human genome and a rich and relatively untapped source of therapeutic drug targets. Unfortunately, the identification of new SLC modulators has been limited. This talk will review recent progress in understanding the structural and molecular basis of SLC transporter function and describe the opportunities these new insights may present for SLC transporter drug discovery.

11:15 Discovery of GLPG2451, a Novel Potentiator for the Treatment of Cystic Fibrosis

Steven Van der Plas, PhD, Group Leader, Medicinal Chemistry, Galapagos

Cystic Fibrosis is caused by mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene, resulting in loss of fuction of the CFTR ion channel. Potentiators are a class of CFTR modulators that allow the effective opening of the CFTR channel by increasing its open probability. I describe the discovery and optimisation of a novel series of potentiators. Additionally, the clinical compound GLPG2451 will be disclosed and its properties will be discussed.

11:45 Spotlight Presentation: Discovery and Pharmacodynamic studies of Potent Dual Norepinephrine and Dopamine Transport Inhibitors

Dean G. Brown, PhD, Director, External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca

12:00 pm Small-molecule CaVα1⋅CaVβ Antagonist Supresses Neuronal Voltage-gated Calcium Channel Trafficking

Samy Meroueh, PhD, Associate Professor, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine

12:30 Luncheon Presentation: Stabilization of Native Membrane Protein Targets for Drug Discovery

Anass Jawhari, CSO, Management,CALIXAR

CALIXAR has developed an innovative detergent/surfactant-based approach for therapeutic membrane protein stabilization. GPCRs, ion channels, transporters can be stabilized without any single mutation, truncation or fusion. We will illustrate that using most recent case studies on targets of high medical relevance for which functional and structural integrities were preserved. This innovative approach represents a serious alternative to classical protein engineering approaches to enable drug discovery (SBDD, FBDD, Antibody Discovery & Vaccine).

1:30 Dessert Break in the Exhibit Hall with Poster Awards Announced

Poster Awards Sponsored by Domainex

GPCR PHARMACOLOGY, KINETICS AND SIGNALING CHALLENGES FOR CHEMISTS

2:15 Chairperson’s Remarks

Dean G. Brown, PhD, Director, External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca

2:20 FEATURED PRESENTATION: One Receptor, Many Partners: How do GPCRs Stimulate Diverse Signaling Proteins?

Ron O. Dror, PhD, Associate Professor, Computer Science, Stanford University

The search for functionally selective or biased ligands that promote GPCR signaling through desired but not undesired pathways represents a major current focus of drug discovery efforts. To enable the rational design of such biased ligands, we are using atomic-level simulations, together with complementary experimental data, to determine how GPCRs cause various intracellular proteins—including arrestins, kinases, and G proteins—to activate and signal.

2:50 The Good, the Bad, and the Confusing: Binding Kinetics at GPCR Targets and Potential Effects on Lead Optimization and Translatability

Brian Murphy, PhD, Senior Principal Scientist, CV and Fibrosis Drug Discovery, Disease Sciences and Biologics, R&D, Bristol-Myers Squibb
Sam Hoare, PhD, Founder, Pharmechanics LLC

Small molecule binding kinetics likely plays an important role in determining both in vitro potency and in vivo efficacy of compounds. For example, compound off-rate may affect the duration of action of compounds in vivo. I will review literature data in support of, and in contradiction to the notion that residence time is a critical factor in compound efficacy in vivo. I will also show examples where in vitro measures of compound affinity and efficacy can be compromised without consideration of compound binding kinetics.

3:20 FEATURED PRESENTATION: GPCRs as Allosteric Sensors Linking Hormone Binding to G Protein Activation to Modulation by Small Molecules and Cations

Roger K. Sunahara, PhD, Professor, Pharmacology, University of California San Diego

G protein-coupled receptors (GPCR) are critical conduits that sense and communicate extracellular stimuli. Their diversity and physiological importance thus make them superb therapeutic targets. Recent advances in the structural biology of GPCRs, along with support from pharmacological and biochemical studies, has helped in understanding the mechanism of GPCR activation and also has been informative for structure-based drug design. We will discuss our recent data on receptor allostery and structure-based drug design of subtype-specific GPCR ligands.

3:50 Networking Refreshment Break

TARGETING PAIN OR THE CNS: OPIOID ALTERNATIVES AND BEYOND

4:20 Chemistry and Pharmacology of Mitragyna Speciosa

Susruta Majumdar, PhD, Associate Professor of Pharmacology, Center for Clinical Pharmacology, St. Louis College of Pharmacy/Washington University

Mitragyna Speciosa, also known as Kratom, originates from the leaves of a tropical tree found in South-East Asia. It has been shown to have pain-relieving properties with less withdrawal effects compared to other opioids. I will discuss the chemistry and pharmacology of Mitragyna Speciosa and present evidence for the biased agonism of the compound.

4:50 Development of D3 Dopamine Receptor Selective Bitropic Ligands

Robert Luedtke, PhD, Professor, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center

I will focus on the development of bitropic D3 dopamine receptor selective ligands for the treatment of cocaine abuse. Though D2 and D3 dopamine receptors have a high level of amino acid sequence homology, we have been able to identify compounds with high binding affinity at the D3 dopamine receptor subtype and that possess greater than 100 fold degree of D3 vs. D2 receptor binding selectivity. Our dopamine GPCR subtype selective ligands resulted from collaborations between medicinal chemists, computational chemists and behavioral pharmacologists.

5:20 Structure, Dynamics and Activation of the CGRP Receptor, a Medically Important Class B GPCR

Christopher Reynolds, PhD, Professor, Royal Society Industry Fellow, School of Biological Sciences, University of Essex

Calcitonin gene-related peptide (CGRP) is a widely expressed neuropeptide; antagonists can be used to treat migraine while agonists are cardioprotective. The CGRP receptor is a heterodimer of the calcitonin receptor-like receptor (CLR) class B G-protein-coupled receptor and the type 1 transmembrane domain protein, receptor activity modifying protein (RAMP) 1. I will present dynamics and activation of the CGRP receptor in complex with the CGRP peptide and the Gs-protein heterotrimer based on our recent 3.3 Å cryo-electron microscopy structure of the human CGRP receptor, photoaffinity labelling studies, and molecular dynamics simulations. Our results also provide novel insights into the role of RAMPs in the activation of the CGRP receptor.

5:50 Close of Conference