Cambridge Healthtech Institute’s 13th Annual

Fragment-Based Drug Discovery

Hits to Leads and Lessons Learned

April 3-4, 2018 | Hilton Bayfront | San Diego, California

Fragment-based drug discovery (FBDD) is migrating from a ‘new/cutting edge’ endeavor to a well-established approach that many companies try when searching for new drug leads. But although there are many ways to find fragments, it is not always easy to choose which hits to pursue or how to advance them to leads. As the original fragment-focused conference in the industry, now in its thirteenth year, we will once again convene diverse experts, from biophysicists to medicinal chemists, as well as newcomers to the field to discuss best practices and hear examples of both successes and failures. The conference will focus on advances in or new screening techniques, integrating information from FBDD campaigns with other lead generation strategies and the challenge of transforming fragment hits to drug leads.

Final Agenda

Tuesday, April 3

7:00 am Registration and Morning Coffee

CHEMISTRY CHALLENGES FOR GROWING FRAGMENTS

8:00 Welcome Remarks

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks

Daniel A. Erlanson, PhD, Co-Founder, Carmot Therapeutics, Inc.

8:10 Creation of a Novel Class of Potent and Selective MTH1 Inhibitors Using Fragment-Based Design

Jenny Viklund, Director, Protein Science and Drug Design, Sprint Bioscience

This presentation describes our fragment-based approach to create potent and selective inhibitors of MTH1 that also have promising drug-like properties. MTH1 is an enzyme involved in degradation of oxidized dGTP to prevent its incorporation into DNA. Enzymes such as MTH which are involved in sanitization of the nucleotide pool have been shown to be important for tumor cell survival.

8:40 Fragment to Lead: SAR and Optimization of Novel Bromodomain Inhibitors with High fsp3 Character

Justin Dietrich, PhD, Senior Scientist III, Discovery Chemistry and Technology, AbbVie, Inc.

This presentation will cover a recent application of AbbVie’s revamped fragment library featuring an example where a fragment with high fsp3 character was quickly advanced to lead with high BEI, LE, and LipE as well as good oral bioavailability. The unique properties associated with fragments with high sp3 character and some lessons learned on the efficiency of chemistry to iterate 3d fragment hits will also be discussed.

9:10 Fragment-Based Screening for Metallo-ß-lactamases Inhibitors: SPR and NMR Combined Approach

Silvia Davalli, Senior Manager, Head, NMR Spectroscopy; Drug Design and Discovery, Aptuit
Metallo-β-lactamases are associated with multidrug resistance in Gram-negative bacteria and their development is a major health concern as there are no clinically-approved drugs up to now. To address the need for novel structurally-diverse inhibitors, we have screened our internal fragment library: information from NMR and SPR techniques are exploited by computational analysis.

9:40 Coffee Break

NOVEL SPR AND NMR APPLICATIONS TO FBDD

10:05 Enabling Alternative Binding Sites with Novel Fragment Screening Approaches Using Surface Plasmon Resonance

Kevin M. O’Malley, PhD, Senior Research Investigator, Lead Discovery, LDO, Bristol-Myers Squibb R&D

Surface Plasmon Resonance (SPR) is an industry standard method for the identification and characterization of fragment hits. Its label free detection using changes in mass make it ideal to definitively confirm target engagement. Typical uses have been to interrogate known binding/active sites. Probing alternative sites can have the advantage of providing novel chemotypes with different modes of interaction with target. Here we describe methods of probing alternate epitopes using conventional and emerging SPR approaches.

10:35 Using NMR-Based Activity Assays to Identify Fragment Leads Against Two Trichomonas Vaginalis Enzymes

Brian Stockman, PhD, Associate Professor and Chair, Chemistry, Adelphi University

Trichomonas vaginalis is classified as a neglected parasitic infection by the CDC, with about 5% of clinical cases resistant to current treatments. Two essential nucleoside ribohydrolase enzymes from T. vaginalis were screened against a fragment library using NMR-based activity assays. Distinct classes of inhibitors with ligand efficiencies greater than 0.5 were identified. Fragment expansion experiments have further improved ligand efficiencies and provided direction to ongoing medicinal chemistry efforts designed to discover nM inhibitors of these enzymes.

11:05 Nanoscale Encapsulation for Optimized NMR Fragment Based Drug Discovery

Josh Wand, PhD, Professor, Biochemistry & Biophysics, University of Pennsylvania

Encapsulation of single protein molecules in reverse micelles is a new and potentially transformative technology. Encapsulation significantly enhances fragment based screening using NMR spectroscopy. The technology in the context of several examples will be described.

11:35 Luncheon Presentation: A Complete Pipeline for Biophysics Based Drug Discovery

Gregg Siegal, CEO, ZoBio

ZoBio has built an integrated technology pipeline that enables a wide array of targets for FBLD and maximizes the chance of successfully generating high quality leads. I’ll discuss all the key elements, including: building a fragment library, using high throughput protein engineering to solve structure problems and better understand target biology, why we use orthogonal fragment screening, and the advantages of having both NMR and X-ray structural biology capabilities.

12:20 pm Session Break

FRAGMENT-ASSISTED DRUG DISCOVERY

1:15 Chairperson’s Remarks

Derek Cole, PhD, Director, Medicinal Chemistry, Takeda

1:20 FEATURED PRESENTATION: The Convoluted Journey of an ERK2 Fragment Series (with an HTS Detour)

Huifen Chen, PhD, Senior Scientist, Discovery Chemistry, Genentech
ERK1/2 represent an essential downstream node in the Ras/Raf/MEK/ERK (MAPK) signal transduction pathway, and have attracted significant interest as potential anticancer targets. Both fragment and high-throughput screens were carried out in parallel to discover novel ERK1/2 inhibitors. In this presentation, I discuss the journey of a fragment-based series along with how learnings from the fragment series were incorporated into the HTS-derived series which led to a clinical candidate GDC-0994.

1:50 Fragment-Based Discovery of Inhibitors of ERK Kinase

Marc O’Reilly, PhD, Senior Director of Molecular Sciences, Astex Pharmaceuticals

This work describes the discovery of highly selective, orally bioavailable, allosteric/bitopic inhibitors of ERK kinase which show robust anti-tumour activity in a range of animal models.

2:20 Discovery of a Ketohexokinase (KHK) Inhibitor for the Treatment of NAFLD/NASH: Fragment-to-Candidate via Structure-Based Drug Design and Parallel Chemistry

Kim Huard, PhD, Senior Principal Scientist, Medicine Design, Pfizer, Inc.

Identification of a selective ketohexokinase (KHK) inhibitor was sought to help elucidate the effect of KHK inhibition on metabolic disorders. In our efforts towards this goal, key structural features interacting with KHK were discovered through fragment-based screening and used to mine our compound collection for attractive chemical starting points. This fragment-to-candidate story will present the fragment-based screen triage, compound optimization via structure-based drug design (SBDD), in vivo target validation and clinical candidate selection.

2:50 Identification of eFT508, an Oral, Potent and Highly Selective Inhibitor of Mitogen-Activated Protein Kinase Interacting Kinase (MNK) 1 and 2, via a Disciplined, Iterative Structure-Based Drug Design Strategy

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

eFT508, an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design beginning with fragments and fragment-like molecules leverages stereoelectronic interactions unique to MNK. eFT508 has potent in vivo anti-tumor activity in models of DLBCL and solid tumors and is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma.

3:20 Present and Futuristic Collaborative Drug Discovery Informatics Innovations (CDD Vault + Bioassay Express)

Barry Bunin, CEO, Collaborative Drug Discovery, Inc.

CDD Vault software, activity & registration, visualization, inventory, and ELN capabilities all address today’s markets. For tomorrow's research: open source descriptors and model sharing capabilities allow for platform-independent collaborations. We've also developed BioAssay Express, human-readable assay text to computer-readable format to augment bioassay needs.

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

4:30 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

4:35 Sponsored Plenary Keynote Introduction (Opportunity Available)

4:40 PLENARY KEYNOTE: Activity-Based Proteomics: Protein and Ligand Discovery on a Global Scale

Benjamin F. Cravatt, PhD, Professor and Co-Chair, Department of Molecular Medicine, The Scripps Research Institute
To address uncharacterized proteins, we have introduced chemical proteomic technologies that globally profile the functional state of proteins in native biological systems. Among these methods is activity-based protein profiling (ABPP), which utilizes chemical probes to map activity states of large numbers of proteins in parallel. I will discuss the application of ABPP to discover and functionally annotate proteins in mammalian physiology and disease, and the generation and implementation of advanced ABPP platforms for proteome-wide ligand discovery.

5:30 Welcome Reception in the Exhibit Hall with Poster Viewing

6:30 End of Day

Wednesday, April 4

7:30 am Continental Breakfast Breakout Discussions

NON-NMR APPROACHES FOR FBDD

8:30 Chairperson’s Remarks

Huifen Chen, PhD, Senior Scientist, Discovery Chemistry, Genentech

8:35 Hot-Spotting with Thermal Scanning: A Ligand- and Structure-Independent Assessment of Target Ligandability

Fredrik Edfeldt, PhD, Associate Principal Scientist, Biophysics, Discovery Sciences, AstraZeneca R&D, Sweden

Evaluating the ligandability of a protein is essential when defining hit-finding strategies or to prioritize amongst drug targets. We demonstrate that high-throughput thermal scanning can be used as a simple and generic biophysical fragment screening method for this purpose. We have applied the method to a large set of proteins and show that the assessment is predictive for the success of HTS. We have also made use of urea and D2O to improve assay sensitivity.

9:05 Weak Affinity Chromatography (WAC): A Novel Approach to Fragment-Based Drug Discovery

Sten Ohlson, PhD, Professor, School of Biological Sciences, Nanyang Technological University

Weak Affinity Chromatography (WAC) is an established analytical affinity technique for specific and gentle separation and analysis of biomolecules. Since its inception in 1990 it has among other applications been successfully used as an efficient tool in drug discovery, mainly for fragment screening. WAC advantages include speed, high quality fragment affinity information, reliable fragment-to-target binding kinetics information and enabling use of a standard LC/MS platform. Examples will be given on screening of membrane proteins (aquaporins), proteases, kinases, coagulation proteins, chaperones and protein-protein interaction (PPI).

9:35 Coffee Break in the Exhibit Hall with Poster Viewing

FRAGMENTS FOR PPIs

10:30 Fragment-Based Discovery of a Chemical Probe for the NSD3-PWWP-1 Domain

Jark Böttcher, Principal Scientist, Medicinal Chemistry, Boehringer Ingelheim RCV GmbH & Co KG

We describe the fragment-based discovery of molecules binding to the proposed methyl-lysine binding site of the PWWP-1 domain of NSD3. Supported by a virtual screening approach and subsequent structure-based optimization, the initial hits were optimized into a chemical probe with confirmed binding in cellular assays. The probe and the related negative control can be used to explore the functions of the PWWP-1 domain.

11:00 Lead Generation without an X-Ray Crystal Structure: An NMR Method to Probe Protein-Ligand Complexes

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

My talk is about a NMR method to solve protein-ligand complex structure. I will present two or three examples of this method applied to finding inhibitors against specific PPI targets.

11:30 In silico Fragment Screening to Identify Cryptic Pockets and Allosteric Sites for PPI Inhibitor Development

Ben Cossins, PhD, Principal Scientist, UCB Pharma

Drug development is increasingly difficult and expensive. Valuable targets are not always amenable to modulation by small molecules and resources are often directed towards seemingly intractable targets. We have been building and applying molecular dynamics based fragment screening and de novo design approaches to try and understand ligandability and functionability for protein-protein interaction targets. We believe this approach can steer us towards hit compounds for tractable PPI targets.

12:00 pm End of Conference