Cambridge Healthtech Instituteの第18回年次会議
Fragment-Based Drug Discovery
2023年4月11 - 12日
*Premium Pricing or separate registration required. See Short Courses page for details.
Registration and Morning Coffee7:00 am
Welcome Remarks8:00 am
CASE STUDIES: FRAGMENT-ASSISTED DRUG DISCOVERY
FEATURED PRESENTATION: Inhibiting TEAD Using Fragment Approaches
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?
Evolving a Fragment-Like Molecule to Multiple Clinical Candidates: Novel Pan-Metallo-β-Lactamase Inhibitors (MBLi) for Potentiation of β-Lactam-Based Antibiotics
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.
Fragment Optimization and Elaboration Strategies - The Discovery of Two Lead Series of PRMT5/MTA Inhibitors from Five Fragment Hits
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.
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.
Networking Coffee Break10:10 am
Attacking Intrinsically Disordered Protein with Fragments
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.
Discovery of Renin Inhibitors via Fragment-Based Drug Design
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.
Drug Repurposing via a Fragment-Based Reconstruction Approach
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
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
Drug Discovery Applications of Covalent Fragments in Neuroscience
Covalent Fragments and Targeting Lysines
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.
Reverse Polarity Activity-Based Protein Profiling
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.
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
Plenary Keynote Introduction (Sponsorship Opportunity Available)4:35 pm
Targeting Nodes and Edges in Protein Networks
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
Registration Open7:00 am
In-Person Group Discussions with Continental Breakfast7:45 am
Developments in Fragment-Based Drug Discovery
- 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
FEATURED PRESENTATION: Fragment Approaches for Discovering Tissue-Specific E3 Ligases and β-Catenin Degraders
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
A New Covalent Fragment Screening Method for Efficient Covalent Drug Discovery
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.
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