Fragment-Based Drug Discovery Icon

Cambridge Healthtech Instituteの第18回年次会議

Fragment-Based Drug Discovery
(フラグメント創薬(FBDD))

低分子ヒットからリードへ、FBDDによる医薬品候補

2023年4月11 - 12日

 

フラグメントベースのリード発見は、創薬における多くのヒット発見スクリーニングキャンペーンに不可欠であり、場合によっては、フラグメント創薬(FBDD)アプローチが、KRASなどの困難な標的に対する進歩を促進しています。創薬業界で最も歴史のある「フラグメントに特化した」会議では、創薬化学者の仲間と集まり、最新の成功事例を聞き、残された課題について議論します。フラグメントベースのスクリーニングでは、他のリード生成アプローチと統合する事例について学びます。フラグメント創薬については、プロジェクトを開始した創薬化学者から体験談を聞くことができます。フラグメントをリードに成長させる場合は、従来の課題について話し合います。フラグメント対応の標的タンパク質分解誘導(TPD)アプローチについては、最新技術について戦略化します。

6:00 pm MONDAY, APRIL 10: Dinner Short Course*
SC2: Fragment-Based Drug Design: Advancing Tools and Technologies

*Premium Pricing or separate registration required. See Short Courses page for details.

4月11日(火)

Registration and Morning Coffee7:00 am

Welcome Remarks8:00 am

CASE STUDIES: FRAGMENT-ASSISTED DRUG DISCOVERY
ケーススタディ:フラグメント支援の創薬

8:05 am

Chairperson's Remarks

Chaohong Sun, PhD, Senior Director, Lead Discovery, AbbVie, Inc.

8:10 am

FEATURED PRESENTATION: Inhibiting TEAD Using Fragment Approaches

Timo Heinrich, PhD, Associate Scientific Director, Oncology, EMD Serono

The deeply buried lipidation pocket (P-site) of the TEAD transcription factors is druggable. The SPR-triggered fragment hit discovery and cellular optimization of a P-site binder are described. Utilizing structure-based design, enhancement in target potency was engineered into the hit, capitalizing on the established X-ray structure of TEAD1 and TEAD3. The efforts culminated in the optimized TEAD1-selective in vivo tool MSC-4106, which exhibited desirable potency, mouse PK properties, and in vivo efficacy. 

  • Can a fragment hit be TEAD-selective?
  • Are P-site sub-pockets suitable for fragment merging?
  • Which technique should be used to identify TEAD surface binding fragments?
8:40 am

Evolving a Fragment-Like Molecule to Multiple Clinical Candidates: Novel Pan-Metallo-β-Lactamase Inhibitors (MBLi) for Potentiation of β-Lactam-Based Antibiotics

Mihir Mandal, PhD, Principal Scientist, Medicinal Chemistry, Merck

Metallo-ß-lactamases, such as NDM-1, VIM-1, and IMP-1 possess poor homology in their active sites.  Despite their poor homology, a class of compounds having a biphenyl tetrazole (BPT) core - identified earlier as a B. fragilis metallo-beta-lactamase inhibitor with weak inhibitory activity against NDM-1 in a biochemical assay - was evolved into pan inhibitor first then into multiple clinical candidates.

9:10 am

Fragment Optimization and Elaboration Strategies - The Discovery of Two Lead Series of PRMT5/MTA Inhibitors from Five Fragment Hits 

Chris Smith, PhD, Executive Director, Drug Discovery, Mirati Therapeutics

Here we report the discovery of two lead series from five fragment hits for our PRMT5/MTA program. The hits were identified via an SPR fragment screen followed by X-ray crystallography. We will outline a two-phase process encompassing fragment optimization followed by fragment growing strategies. Access to versatile synthetic intermediates, synthetic traceability, and enablement of structure-based drug design were important success factors. Further optimization of potency, selectivity, and pharmacokinetic parameters resulted in the discovery of MRTX1719. MRTX1719 is currently in a Phase 1/2 clinical study in solid tumors with MTAP-deletion.  

9:40 am Using WAC™ for Identification and Characterization of a Novel Binding Site on the SMARCA4 Bromodomain

Kirill Popov, PhD, Head of FBLD, Weak Affinity Chromatography WAC

WAC™ was used to perform a fragment screen towards the bromodomain of SMARCA4. In addition to hits binding to the KAc site, some hits bound to a second site outside the KAc pocket. Here we present hit validation and expansion efforts toward this novel site.

9:55 am Talk Title to be Announced

Tony Huxley, Head of Business Development, Business Development, Liverpool ChiroChem Ltd.

Networking Coffee Break10:10 am

10:35 am

Attacking Intrinsically Disordered Protein with Fragments

Haihong Wu, PhD, Senior Scientist II, Global Protein Sciences, AbbVie, Inc.

Aggregation of the tau, an intrinsically disordered protein (IDP), into neurofibrillary tangles is one of the hallmarks of Alzheimer’s disease (AD). In this presentation, we discuss a fragment-based approach, employing protein NMR, to discover tau binders that could potentially disrupt tau aggregation. Chemical elaboration of fragment hits, driven by both NMR and surface plasmon resonance (SPR), resulted in tau binders with affinities in the low double-digit micromolar range.

11:05 am

Discovery of Renin Inhibitors via Fragment-Based Drug Design

Tanweer A. Khan, PhD, Director & Head, Discovery Chemistry, ATAI Life Sciences

Renin is an aspartic protease enzyme and the development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. Based on initial BACE1 inhibitors, a repertoire iminopyrimidinones is a novel pharmacophore for aspartyl protease inhibition. In this presentation, we describe how we leverage structural information from the database and modified substitution around this pharmacophore to develop a potent, selective, and orally active renin inhibitor.

11:35 am

Drug Repurposing via a Fragment-Based Reconstruction Approach

Xavier Morelli, PhD, Director of Research, Cancer Research Center of Marseille, CNRS

The discovery/development of new drugs is a highly costly and slow process while repositioning old drugs to treat other diseases is increasingly becoming an attractive proposition. In this context, at the interface between drug design and drug repositioning, we decided to apply our integrative multidisciplinary drug design approach, DOTS, to deconstruct and optimize an existing drug in a Structure-Based ‘Hit-to-Lead’ optimization approach on a newly validated target. In the present study, we designed a ‘derivative’ library of the deconstructed drug by gradually implementing key chemical modifications in an automated process to increase protein-ligand interactions and activity toward the new target.

Transition to Lunch12:05 pm

12:15 pm LUNCHEON PRESENTATION:FragmentDEL-DNA-Encoded Libraries of Fragments for Hit Discovery for Challenging Targets

Rod Hubbard, Professor, Founding Scientist, Director of Research Collaborations, Vernalis (R&D) Ltd.

Combining the sensitivity of DEL and chemical space coverage of fragments is a new approach for identification of hit compounds for challenging targets.  This has been demonstrated with PAC-FragmentDEL, where photoactivation captures the fragment binding to the target.  As well as describing additional applications this approach, I will describe the design and use of other ideas for FragmentDELs.

Session Break12:45 pm

COVALENT FRAGMENTS
共有結合フラグメント

1:30 pm

Chairperson's Remarks

Mela Mulvihill, PhD, Director and Senior Principal Scientist, Biochemical & Cellular Pharmacology, Genentech, Inc.

1:35 pm

Drug Discovery Applications of Covalent Fragments in Neuroscience

Jeffrey Martin, PhD, Scientist II, Drug Discovery, Biogen

An overview of reactive cysteines in neuroscience focused research will be discussed. Approaches for covalent fragment screening and drug discovery applications will also be covered.

2:05 pm

Covalent Fragments and Targeting Lysines

Maurizio Pellecchia, PhD, Professor, Biomedical Sciences Division, University of California, Riverside

Drug discovery approaches aimed at designing targeted covalent inhibitors are currently heavily pursued by academia, biotech, and pharmaceutical companies. These approaches have culminated in the recent approval of several Cys-covalent drugs in oncology. With the resurgence and the success of such covalent drugs, our studies focus on the identification of novel and effective design strategies that widen the available target space beyond cysteine, to include other more abundant residues such as lysine, tyrosine, or histidine. I will report on fragment- and structure-based strategies that include the design of potent and selective Lys- and His-covalent agents targeting oncogenic proteins.

2:35 pm

Reverse Polarity Activity-Based Protein Profiling

Megan L. Matthews, PhD, Assistant Professor, Chemistry, University of Pennsylvania

The polar chemistry of activity-based protein profiling (ABPP) probes was reversed by deploying the nucleophilic hydrazine pharmacophore found in old CNS drugs to show organohydrazines are active-site directed and mechanism-based inhibitors of protein classes that are difficult to drug. Using the first N-nucleophile fragment/probe library, we showed that potent and selective inhibitors can be developed and that reverse-polarity ABPP can advance small molecules that modulate diverse electrophile-dependent functions.

3:05 pm Leveraging Cryo-Electron Microscopy to Reshape Drug Discovery Landscape

Surajit Banerjee, Dr., Sr. Product Specialist, Life Sciences, Materials & Structural Analysis Division, Thermo Fisher Scientific

Cryo-EM has evolved to a mainstream structural biology method and a game-changing technology for structure-based drug discovery of challenging targets. It was adopted as a well-established technique in the pharmaceutical industry due to its ability to visualize macromolecular assemblies and investigate the intricate interactions between drugs and receptors. How Cryo-EM rapidly overcoming its limitations for more widespread usage through a new wave of technological advances, will be discussed.

Refreshment Break in the Exhibit Hall with Poster Viewing3:20 pm

PLENARY KEYNOTE SESSION
基調講演(プレナリーセッション)

4:20 pm

Plenary Welcome Remarks from Lead Content Director with Poster Finalists Announced

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

Plenary Keynote Introduction (Sponsorship Opportunity Available)4:35 pm

4:45 pm PLENARY:

Targeting Nodes and Edges in Protein Networks

Michelle Arkin, PhD, Chair and Distinguished Professor, Pharmaceutical Chemistry & Director, Small Molecule Discovery Center, University of California, San Francisco

Protein interaction networks consist of protein nodes and interaction edges. We aim to inhibit or stabilize specific protein-protein interactions to dissect these complex networks for chemical biology and therapeutics discovery. Through covalent fragment-based approaches, we discovered compounds that selectively stabilized the chaperone 14-3-3 bound to diverse client proteins and altered their function. Additionally, function-selective inhibitors for the multifunctional enzyme VCP/p97 are providing new tools and drug leads for cancer.

Welcome Reception in the Exhibit Hall with Poster Viewing5:30 pm

Close of Day6:30 pm

4月12日(水)

Registration Open7:00 am

In-Person Group Discussions with Continental Breakfast7:45 am

IN-PERSON GROUP DISCUSSION:

Developments in Fragment-Based Drug Discovery

Ben J. Davis, PhD, Research Fellow, Biology, Vernalis R&D Ltd.

Mela Mulvihill, PhD, Director and Senior Principal Scientist, Biochemical & Cellular Pharmacology, Genentech, Inc.

  • Progressing fragments without routine structural data 
  • How to evolve extremely weak fragments (X-ray crystallography (low cost possible?), cryo-EM)
  • Innovations for FBDD (DNA-encoded libraries for fragments?)
  • FBDD for challenging targets (RNA, ion channels, complex assemblies, disordered proteins)
  • Can fragments speed TPD discovery? 
  • Covalent fragment applications

FRAGMENTS AND TARGETED PROTEIN DEGRADATION APPROACHES
フラグメントと標的タンパク質分解誘導アプローチ

8:30 am

Chairperson's Remarks

Daniel A. Erlanson, PhD, Senior Vice President, Innovation and Discovery, Frontier Medicines Corporation

8:35 am

FEATURED PRESENTATION: Fragment Approaches for Discovering Tissue-Specific E3 Ligases and β-Catenin Degraders

Stephen W. Fesik, PhD, Professor of Biochemistry, Pharmacology, & Chemistry; Orrin H. Ingram II Chair in Cancer Research, Vanderbilt University

I will present how we've applied fragment-based methods to discover ligands for tissue-specific E3 ligases. I will also cover our work on discovering bifunctional degraders for β-catenin. This highly sought-after but difficult-to-drug intracellular target is part of a multi-functional cellular signaling complex whose overactivity contributes to the development of specific cancers and other diseases.

Coffee Break in the Exhibit Hall with Poster Awards Announced9:35 am

Poster Award (Sponsorship Opportunity Available)

FRAGMENTS, COVALENT INHIBITORS, KRAS
フラグメント、共有結合阻害剤、KRAS

10:30 am

A New Covalent Fragment Screening Method for Efficient Covalent Drug Discovery

Jim Nonomiya, Scientist IV, Biochemical and Cellular Pharmacology, Genentech, Inc.

The discovery of a targetable cryptic pocket in KrasG12C has ignited interest in covalent targeting and, in particular, fragment-based screening approaches to identify covalent ligands for difficult-to-drug targets. I will introduce a novel screening method that aims to streamline the covalent drug discovery process by simultaneously providing binding site information.

11:00 am

Fragment Library Screening for Covalent RAS Inhibitors

Samy O. Meroueh, PhD, Associate Professor, Biochemistry & Molecular Biology, Indiana University

I will present our K-RAS covalent fragment screening that led to identification of fragments that react at two novel sites on K-RAS.

11:30 am

NMR and KRAS Fragments

Julien Orts, PhD, Assistant Professor, Physical Chemistry Lab, ETH Zurich

We will disclose several fragment structures and new NMR approaches dedicated to KRAS. 

12:00 pm Biophysical and Structural Biology Methods Enable Fragment-based Covalent Ligand Discovery of Human BTK

Moran Jerabek-Willemsen, Head of Biophysics & Screening, WuXi HitS, WuXi AppTec

Powerful biophysical and structural biology tools enable the study of large numbers of covalent fragments and are opening up new possibilities in the treatment of various diseases. Here we report the results of a covalent FBDD project on Bruton’s Tyrosine Kinase (BTK) and show how orthogonal biophysical and structural methods enable rapid identification, characterization, and optimization of covalent fragments.

Close of Fragment-Based Drug Discovery Conference12:15 pm

Dinner Short Course*6:15 pm

SC8: Biophysical Tools for Membrane Proteins: Drug Discovery Applications

*Premium Pricing or separate registration required. See Short Courses page for details.

* 不測の事態により、事前の予告なしにプログラムが変更される場合があります。

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