Cambridge Healthtech Institute 第13回
Fragment-Based Drug Discovery
( フラグメントベースの創薬 )
2018年4月3-4日 | Hilton Bayfront | カリフォルニア州サンディエゴ
フラグメントベースの創薬 (FBDD) は、「最先端の」試みから、新たなリード化合物を探すため多くの企業が採用する確立した手法へと進化しつつあります。シンプルで小さな化合物 (フラグメント) を見つける方法は数多く存在しますが、研究を推進すべきヒット化合物やリード化合物へと発展させる方法を選択する作業は必ずしも容易ではありません。フラグメントベースの創薬をテーマにした他に類を見ないこのカンファレンスプログラムでは、生物物理学や医薬品化学などさまざまな分野の専門家が、この分野での経験が浅い研究者も交えて、ベストプラクティスについて議論し、失敗と成功双方の事例について考えます。今回は、新たなスクリーニング手法、FBDDプロジェクトから得られた情報を他のリード化合物開発プロジェクトに統合するための取り組み、フラグメントのヒット化合物をリード化合物への転換するうえでの課題などのトピックが焦点となります。
7:00 am Registration and Morning Coffee
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, PhD, Principal Scientist, Computational Chemistry, 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.
Silvia Davalli, Senior Manager, Head, NMR Spectroscopy; Drug Design and Discovery, Aptuit
9:40 Coffee Break
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
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, Department of Biophysics, 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 Plenary Keynote Introduction
Kevin Lustig, PhD, CEO, Scientist.com
4:40 PLENARY KEYNOTE: Targeting Ras and MYC for the Treatment of Cancer
Stephen Fesik, PhD, Professor of Biochemistry, Pharmacology, and Chemistry, Orrin H. Ingram II Chair in Cancer Research, Vanderbilt University School of Medicine
Two of the most important targets in cancer are Ras and MYC. However, both of these highly validated cancer targets are thought to be undruggable. In this presentation, I will discuss our approaches for targeting both of these proteins directly and indirectly using fragment-based methods and structure-based design.
5:30 Welcome Reception in the Exhibit Hall with Poster Viewing
6:30 End of Day
Day 1 | Day 2
7:30 am Continental Breakfast Breakout Discussions
8:30 Chairperson's Remarks
Ben Davis, PhD, Research Fellow, Biology, Vernalis Research
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
10:30 Fragment-Based Discovery of a Chemical Probe for the NSD3-PWWP-1 Domain
Jark Bottcher, 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