Cambridge Healthtech Institute’s 14th Annual

Fragment-Based Drug Discovery

From Hits to Leads and Lessons Learned

April 9-10, 2019

Fragment-based drug discovery (FBDD) has proven to be a successful approach for finding new drug compounds, especially against difficult targets such as intracellular protein-protein interactions (PPIs). Quite a few drugs on the market today can trace their origins to hits from fragment-based library screening campaigns. Now that FBDD has been folded into many early drug discovery departments, questions such as how to merge hits arising from fragment-based screens with hits from traditional high throughput screening methods are more frequent. Plus, the challenge of growing fragment hits into drug leads still remains, especially when the fragment and target do not have co-crystal structures to guide ligand design. Discuss these questions and more at Cambridge Healthtech Institute's 14th annual Fragment-Based Drug Discovery conference, the original FBDD meeting of the industry. We will continue our tradition of providing a forum for leaders and practitioners in the field to learn from one another by sharing success stories and challenges.

Final Agenda

Tuesday, April 9

7:00 am Registration Open and Morning Coffee (20 C/D Foyer) 

FBDD SUCCESS STORIES
31 B/C

8:00 Welcome Remarks

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

8:05 Chairperson’s Opening Remarks

Dan Erlanson, PhD, Co-Founder, Carmot Therapeutics

8:10 Application of Fragment-Based Drug Discovery in the Identification of Novel FXIa Inhibitors for Thrombosis Prevention

Santhosh F. Neelamkavil, PhD, Director, Discovery Chemistry, Merck Research Laboratories

Fragment-based drug design has the potential to deliver hits to lead optimization with improved properties and aims to reduce compound-related attrition in clinic. We have been interested in the mechanism of FXIa inhibition, as this target has the potential for anti-coagulative activity with reduced bleeding liability. Here we will describe our efforts to identify a novel fragment hit, which was then elaborated to identify a series of potent FXIa inhibitors.

8:40 An Alternate Inhibition Mechanism for the Deubiquitinase USP7 and its Consequences for Ubiquitin Chain Linkage Selectivity

Till Maurer, PhD, Director, NMR-Lead, Analytical Enabling Technologies, Merck; formerly: Senior Scientist, Structural Biology, Genentech Inc. 

USP7 inhibition is a bona fide P53 stabilization mechanism. Using a fragment based lead discovery approach we (at Genentech) found small molecule ligands with a non-active site mechanism to inhibiting USP7. Binders to an acidic patch in the USP7 catalytic domain interfere with the binding of Ubiquitin and Ubiquitin chains. This finding allowed us to delineate how different Ubiquitin chain linkages are recognized and determine that specific interactions are responsible.

9:10 Development of gamma-Secretase Modulators for the Treatment of Alzheimer’s Disease

R. Jason Herr, PhD, Research Fellow, Medicinal Chemistry Department, AMRI

Alzheimer’s Disease is characterized medically by an accumulation of plaques in the brain composed primarily of a 42-amino acid protein called amyloid β (Aβ42). One therapeutic approach currently being tested in the clinic is to use small molecule drugs to interfere with the function of the enzyme gamma-secretase. This enzyme has several important biological roles, but in the disease state its task is to produce the toxic protein Aβ42. This talk will describe a program designed to develop drugs to disrupt the ability of gamma-secretase to produce Aβ42, but still allow it to carry out its positive functions. One such gamma-secretase modulator (GSM) has moved forward into preclinical testing.

9:25 High-Throughput Fragment Screening by Weak Affinity Chromatography (WAC)

Björn Walse, CEO, SARomics Biostructures/Red Glead Discovery

The advantages of WAC™ for FBS are the detection of weak binders by screening fragments at low concentrations (<5 &mu;M) and its immediate ranking of hits. Here we present a USP7 WAC™ screen and its use for rapid establishment of SAR by analogue screening and downstream validation by biophysical techniques.

9:40 Networking Coffee Break

10:05 The Discovery of Novel Allosteric MEK1 Binders by Fragment-Based Approaches

Paolo Di Fruscia, PhD, Senior Scientist, Structure Biophysics & FBLD, Discovery Sciences, IMED Biotech Unit, AstraZeneca UK

MEK1 has been pursued as a target in AZ for the treatment of COPD. To develop structurally novel MEK1 inhibitors, suitable for inhalation strategies, a combination of virtual, biophysical and X-ray fragment screening technologies were explored. The fragment campaign returned several efficient hits co-binding with ATP in a well-established binding site. A few series were progressed and one elaborated into completely novel sub-μM equity.

10:35 Fragment-Based Drug Discovery Campaigns with Protein Complexes that Mediate Protein-Protein Interactions

Charles Wartchow, PhD, Senior Investigator, Novartis Institutes for Biomedical Research

We performed FBS campaigns with protein complexes from several disease areas and proteins involved in protein degradation. These campaigns present unique challenges; hit validation requires important counter screens to identify binding location and data interpretation can be more challenging than for monomeric targets. Methods used in successful campaigns include combinations of SPR, NMR, DSF, XRC and Biodesy’s second-harmonic generation (SHG) platform. These methods identify and validate the binding of fragments to key functional regions of proteins and in unexpected locations.

11:05 Busted! Recognizing False Positives and False Negatives: Learnings from Comparative Analysis of Fragment Binding using X-Ray Crystallography and NMR

Engi Hassaan, MSc, PhD Fellow, Laboratory of Gerhard Klebe, Pharmaceutical Chemistry, Philipps University in Marburg, Germany

X-ray crystallography provides structural information that is crucial for fragment optimization, however there are several criteria that must be met for a successful fragment screening including the production of soakable and well-diffracting crystals. Frequently, reliable cascades of screening methods are applied as pre-screens prior to labor-intensive X-ray crystallography which appears on first sight a beneficial strategy. We have done follow-up studies to investigate whether different screening methods will reveal similar collections of putative binders. The detailed comparative analysis of the findings obtained by the different methods, including which method is less likely to produce false negatives and false positives, will be presented in the talk.

11:35 Luncheon Presentation: Emerging Topics in Protein Production for Biotechnology: Challenges, Opportunities

Tara Davis, PhD, Senior Scientist, X-Ray Crystallography, FORMA Therapeutics

Quality protein production, whether implemented internally or externally, is critical for successful drug discovery. Current trends in biotechnology towards study of difficult protein classes, PPI and allosteric targets, intrinsically disordered regions, biologics, and multi-protein complexes present unique challenges for early discovery protein sciences teams. Addressing these challenges will likely combine innovative modification of existing technologies, thoughtful integration of CRO expertise, and new approaches to pipeline strategy, e.g. utilizing AI/machine learning algorithms to overcome pipeline roadblocks. A broad overview of these topics will be discussed, with the hope of encouraging further discussion throughout the conference.

12:20 pm Session Break

NEW FBDD APPROACHES

1:15 Chairperson’s Remarks

Maricel Torrent, PhD, Principal Research Scientist, Molecular Modeling, AbbVie

1:20 Pushing the Envelope for Fragment-Based Drug Discovery (FBDD) with ‘MiniFrags’

Marc O’Reilly, DPhil, Senior Director, Molecular Sciences, Astex Pharmaceuticals

This talk will describe how Astex is employing protein crystallography and ultra high concentration, aqueous, MiniFrag ligand soaking to inform early stage drug discovery.

1:50 Fragment Library Design; Quantitative Analysis of Molecular Shape and Functionality

Paul Colbon, PhD, CEO, UK Headquarters, Liverpool ChiroChem, Ltd.

This presentation introduces the development of a new parameter, Vector Efficiency (VE), that guides considerations of vector space within the fragment library design process. This quantitative parameter measures the vector space coverage of the key functionalities (e.g. HBD’s, HBA’s, lipophilic groups) within a fragment library. Optimally designed libraries achieve the broadest coverage of vector space from the smallest number of compounds.

2:20 Solvation Energy-Driven Docking in Library Design: Applications to Fragment-Based and Fragment-Assisted Approaches

Pawel Sledz, PhD, Senior Scientist, Department of Biochemistry, University of Zurich

Fragment screening libraries suffer from low hit rates, in particular against difficult targets like PPI or proteins interacting with nucleic acids. For the design and assembly of target-focused libraries we developed a very efficient computational screening approach based on evaluation of solvation energies of fragments. By several examples I will illustrate how our approach allows for more efficient exploration of vast chemical space and significantly reduces the costs of early screening efforts, by enriching libraries in potential hits.

2:50 Playing with Water: from Weak Binders to Potent Inhibitors of the Oncogenic Transcription Factor BCL6

Sven Hoelder, PhD, Professor, Medicinal Chemistry and New Drug Design, Institute of Cancer Research

BCL6 is an oncogenic transcriptional repressor that contributes to the pathology of blood cancers, particularly lymphomas and acute leukaemias. Its oncogenic activity relies on the ability to recruit transcriptional co-repressors through its BTB domain. Inhibition of this protein-protein interaction is an attractive therapeutic approach. In this talk, we will present the discovery of nanomolar inhibitors starting from weak binders and particularly highlight the crucial role of water molecules in the binding site.

3:20 The Goldilocks Zone for Research Informatics - Next Generation Tools That Support Discovery Organizations of All Sizes

Whitney Smith, PhD, Director, Business Development, Collaborative Drug Discovery, Inc.

Unlike traditional informatics that force you to choose between “complete, complicated, and expensive” vs “cheap, easy, and mostly-useless”, CDD’s Vault and BioAssayExpress affordably deliver comprehensive, secure, easy-to-use, and performant SaaS informatics for discovery teams. We’ll discuss how this works and why it’s necessary in today’s fast-moving and collaboration-heavy research environment.

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Plenary Session Welcome Remarks from Event Director

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

4:35 Plenary Technology Spotlight: Molecular Modelling for the Masses: Orion

Paul Hawkins, Head, Scientific Solutions, OpenEye Scientific

The advent of cloud computing has been transformative for many fields that utilize computation, including drug discovery. The cloud offers robust, elastic, and scalable compute resources through a browser, decreased IT overhead, costs, and time to obtain actionable results. In this presentation I illustrate how the cloud, and in particular OpenEye’s web-based platform Orion, is democratizing molecular modelling by providing easy to use access to cutting-edge molecular design tools coupled with essentially unlimited compute resources.

5:05 Plenary Keynote Introduction

Vicky Steadman, PhD, Business Line Leader, Integrated Drug Discovery, Eurofins Discovery (formerly Eurofins Pharma Discovery Services)

5:10 Plenary Keynote: Chemical Biology of Proteostasis

Jack Taunton, PhD, Professor, Department of Cellular and Molecular Pharmacology, University of California San Francisco

We have recently discovered several macrocyclic compounds that potently and selectively modulate protein homeostasis. I will discuss our recent efforts to unravel their molecular mechanisms.

6:00 Welcome Reception in the Exhibit Hall with Poster Viewing

7:00 Close of Day

WEDNESDAY, APRIL 10

7:30 am Continental Breakfast Breakout Discussions - View All Breakouts

FRAGMENT-DERIVED DRUG CANDIDATES PROGRESSING IN THE CLINIC

8:30 Chairperson’s Remarks

Robert D. Mazzola, PhD, Director, Chemical Research, Merck Research Labs

8:35 FEATURED PRESENTATION: Discovery of ABL001, an Allosteric Inhibitor of Bcr-Abl Kinase

Wolfgang Jahnke, PhD, Director and Leading Scientist, Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research

The team effort that led to the discovery and early development of ABL001 will be described. Discovery of ABL001 started with a fragment-based screen using NMR spectroscopy and X-ray crystallography. An NMR-based conformational assay was needed to understand the requirements for functional inhibition of fragments. Structure-based design and medicinal chemistry finally resulted in the clinical candidate ABL001, which is currently in phase III trials of chronic myelogenous leukemia.

9:05 BACE Inhibitor Drug Discovery - From Fragment-Based Hits to Clinical Candidates

Erik J. Hembre, PhD, Research Fellow, Discovery Chemistry Research, Eli Lilly & Co.

Fragment based drug discovery is a powerful technique to identify starting points for difficult to drug targets. A case in point is BACE1, a key enzyme involved in the production of amyloid-beta peptides and the amyloid plaques associated with Alzheimer’s disease. Enabled by a fragment-based approach, we identified a weak but efficient amino-thiazine hit structure that ultimately led to the delivery of three BACE1 clinical candidates, LY2811376, LY2886721, and LY3202626.

9:35 Coffee Break in the Exhibit Hall with Poster Awards Announced

Poster Awards Sponsored by Domainex

FRAGMENTS AND PPIs

10:30 FEATURED PRESENTATION: Molecular Glues for Protein-Protein Interactions: A Fragment-Based Approach to Stabilize 14-3-3/Client Complexes

Michelle Arkin, PhD, Professor, Department of Pharmaceutical Chemistry, University of California San Francisco

Many proteins have multiple binding partners, potentially inducing different biological effects. Stabilizing such protein-protein interactions offers an opportunity to dial in specificity for both partners, and can be inhibitory, activating, or synthetic. Our team is developing specific stabilizers of 14-3-3/client proteins to evaluate the scope and limitations of these effects. This talk will describe our initial foray in the 14-3-3 stabilization using fragment-based drug discovery approaches.

11:00 Biophysics and Structural Biology offer a Direct Path to Allosteric Drugs

Gregg Siegal, CEO, ZoBio

Allosteric drugs offer exciting new opportunities. ZoBio's platform of biophysics and structural biology allows us to design campaigns that directly seek allosteric modulators of pharmaceutical targets. I will illustrate this capability using HSP70 as an example. HSP70 is a validated target in both oncology and neurodegeneration and yet, has proven challenging to drug. The process used to develop compounds that are selective for the ADP-bound form and inhibit ATPase activity will be described.

11:30 Fragment Philosophy Used in the Identification of eFT508, an Oral, Potent and Highly Selective Inhibitor of Mitogen-Activated Protein Kinase Interacting Kinase (MNK) 1 and 2

Paul Sprengeler, PhD, Research Fellow, Medicinal Chemistry, eFFECTOR Therapeutics, Inc.

Starting from a handful of fragments and fragment-like molecules, the crystal structure-guided approach, leveraging stereoelectronic interactions, to eFT508, an exquisitely selective, potent dual MNK1/2 inhibitor, will be presented. eFT508 was designed to assess the potential for control of oncogene signaling at the level of mRNA translation and has shown potent in vivo anti-tumor activity in models of DLBCL and solid tumors. It is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma.

12:00 pm Close of Conference