Cambridge Healthtech Institute 第14回
Fragment-Based Drug Discovery
( フラグメントベースの創薬 )
フラグメントベースの創薬 (FBDD) は、新薬となる可能性のある化合物を発見するための有効なアプローチとして認められており、特に細胞内でのタンパク質間相互作用などの困難な標的で優れた成果をあげています。現在市場に投入されている医薬品のなかには、フラグメントベースのライブラリースクリーニングキャンペーンで発見されたヒット化合物が起源となっているものも少なくありません。すでにFBDDは、多くの製薬会社で創薬初期段階の工程に組み込まれていますが、フラグメントベースのスクリーニングで得られたヒット化合物と従来のハイスループットスクリーニング法で得られたヒット化合物をどのように融合させるのかといった課題に直面するケースも増えています。また、フラグメントベースのヒット化合物をリード化合物へと成長させるうえでの課題は解決されておらず、とりわけフラグメントと標的がリガンド設計の指針となる共結晶構造を持たない場合には大きな問題となります。フラグメントベースの創薬をテーマにしたこのカンファレンスプログラムは、製薬業界を対象としたFBDDに関する学会の草分けであり、この分野に携わっているさまざまな組織の幹部や実務担当者が成果や課題についての意見交換を通じて知識を吸収することができる場を提供するという役割を担い続けています。
Day 1 | Day 2
Tuesday, April 9
7:00 am Registration Open and Morning Coffee
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)
Speaker to be Announced
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 Hassan, 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 to be Announced
12:20 pm Session Break
1:15 Chairperson’s Remarks
Maricel Torrent, PhD, Senior Scientist III, 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 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 Welcome Remarks from Lead Conference Director
Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute
4:35 Plenary Technology Spotlight Presentation to be Announced
5:05 Plenary Keynote Introduction (Sponsorship Opportunity Available)
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
Day 1 | Day 2
WEDNESDAY, APRIL 10
7:30 am Continental Breakfast Breakout Discussions - View All Breakouts
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
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