( 领导化合物的创造策略 )
Finding new drug leads for medical conditions with unmet solutions is one of the biggest hurdles in recent drug discovery as the ‘obvious’ drug candidates have already been found. Plus, there are more molecular targets to develop new drugs against thanks to the rapid pace of medical research. Many of these new molecular targets are more complex, such as protein-protein interactions (PPIs) or protein-nucleic acid complexes and move ‘drug hunters’ into less explored chemical space from which to find or design appropriate lead compounds. Luckily, synthetic chemistry and other innovations have expanded the chemical space new drug leads can occupy while still fitting the properties of a ‘good drug’. Join fellow discovery chemists and biologists at the Lead Generation Strategies conference to review the various advances and strategies for finding and creating novel drug leads in today’s expanded chemical and molecular universe.
Day 1 | Day 2
1:00 pm Pre-Conference Short Course Registration
Click here for details on short courses offered.
7:00 am Registration Open and Morning Coffee
Progressing From Target Hits To Drug Leads
8:00 Organizer's Welcome Remarks
8:05 Chairperson’s Opening Remarks
Robert D. Mazzola, PhD, Director, Chemical Research, Merck Research Labs
8:10 FEATURED PRESENTATION: Interplay between Lead Generation and Target Validation in AbbVie Early Chemistry: A Wild-Type Isocitrate Dehydrogenase 1 Case Study
J. Brad Shotwell, PhD, Senior Principal Scientist, Tool and Lead Generation Chemistry Group Leader, AbbVie
Inhibition of wild type isocitrate dehydrogenase 1 (IDH1), a key source of cytosolic NADPH under conditions of cellular stress, represents an inroad for treatment of VHL-null mutant renal cell carcinomas. We will summarize AbbVie’s IDH1 lead-finding activities as they inform both best practices for an integrated hit confirmation approach and the critical interplay between small molecule lead generation and the pharmacological testing of novel target hypotheses.
8:40 Exploiting Pilot Screen Hits to Pressure-Test HTS Screening Triage Funnels
Michael Finley, PhD, Principal Scientist, Screening, Discovery Sciences, Janssen R&D
High-throughput screening (HTS) of small molecule libraries requires careful consideration of potential off-target mechanisms that may contribute to false positives or mask identification of on-target active compounds. Employing a pilot screen of representative chemotypes of the larger collection provides a means to pressure test a triage strategy with initial hits. We illustrate several examples in which pilot data were used to identify and address gaps in HTS triage.
9:10 Encoded Library Technologies as Integrated Lead Finding Platforms for Drug Discovery
Jonas V. Schaefer, PhD, Laboratory Head, Encoded Library Technologies, Novartis Institutes for Biomedical Research, Chemical Biology & Therapeutics (CBT), Novartis Pharma AG
The scope of targets investigated in pharmaceutical research is continuously moving into uncharted territory. Consequently, finding suitable chemical matter with the current compound collections is proving increasingly difficult. Encoded library technologies allow for the rapid exploration of a large chemical space for the identification of ligands for such targets. In the presentation, we will discuss how we apply these platforms in our research, including how we narrow the myriad of hits to a few leads, and why we believe it is beneficial to run both pipelines in-house.
9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
10:25 A Phenotypic Screen for ALS
Dean G. Brown, PhD, Director, External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca
10:55 Phenotypic Screening and Chemical Biology Strategies to Identify Mechanisms that Regulate Brain Apolipoprotein E Levels
Martin Pettersson, PhD, Associate Research Fellow, Internal Medicine & Medicinal Chemistry, Pfizer
Apolipoprotein E (ApoE) is a 34 kDa protein that functions as a transporter of cholesterol and phospholipids in both the brain and the periphery. In the brain, it is produced primarily by astro-cytes, and plays an important role in neuronal repair, synaptogenesis, and clearance of neurotoxic amyloid β peptides. This presentation will describe phenotypic screening approaches to identify compounds that regulate ApoE secretion. Chemical biology strategies to elucidate mechanism of action will also be discussed.
11:25 CryoEM Applications for Drug Discovery
Seungil Han, PhD, Associate Research Fellow, Structure Biology & Biophysics, Pfizer Global R&D
11:55 Preclinical Approaches to Develop Treatment for Tinnitus
Sylvie Pucheu, CSO, CILcare
Tinnitus is usually perceived as an intermittent or continuous sound. There are many mechanisms inducing tinnitus (acoustic trauma, drug intake, oxidative stress, inflammation), for which there are no approved drugs. This is why CILcare proposes preclinical approaches to help pharmaceutical companies develop new therapies to prevent and treat tinnitus.
12:10 pm Presentation to be Announced
12:25 Session Break
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:15 Refreshment Break in the Exhibit Hall with Poster Viewing
Covalent Fragments As Drug Discovery Tools
1:50 Chairperson’s Remarks
Beth Knapp-Reed, PhD, Scientific Leader, NCE-MD Medicinal Chemistry, R&D
Platform Technology & Science, GSK
1:55 Use of Chemotype Evolution to Discover Novel, Potent, Irreversible Inhibitors of the Oncogenic G12C Mutant Form of k-RAS
Dan Erlanson, PhD, Co-Founder, Carmot Therapeutics
The protein KRAS has been intensively studied as an oncology target. This presentation will demonstrate how a powerful lead discovery technology, Chemotype Evolution, along with medicinal chemistry and structure-based drug design, were combined to discover novel, irreversible small molecule inhibitors of the oncogenic G12C mutant form of KRAS with potent biochemical and cell-based activity.
2:25 Reactive-Cysteine Profiling for Covalent Ligand Discovery
Eranthie Weerapana, PhD, Associate Professor, Department of Chemistry, Boston College
Reactive and functional cysteine residues provide ideal anchors for covalent ligands. This presentation will focus on the application of a chemical-proteomic technology, known as isoTOP-ABPP, to identify functional cysteines, and monitor proteome-wide selectivity of cysteine-targeted ligands.
2:55 Presentation to be Announced
3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
4:05 Covalent Fragments Technology for Drug Lead Generation: Past, Present, and Future
Alexander Statsyuk, PhD, Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of Houston
Covalent fragments is a new lead generation technology, which rests on principles of covalent drug design and fragment-based drug discovery. The main advantage of covalent fragments relative to reversible fragments is that they have enhanced potency and that crystal structures of covalent fragments bound to protein targets can readily be obtained. I will talk about the use of this technology to discover E3 ligase inhibitors and the technology’s future applications in target-based and phenotypic screens.
4:35 Applying Covalent Fragment Approaches to E3 Ligase Inhibitor Discovery
Katrin Rittinger, PhD, Professor, Molecular Structure of Cell Signaling, The Francis Crick Institute, UK
Protein ubiquitination is a critical mechanism to regulate almost all biological processes and defects in the ubiquitin system that are associated with many diseases. However, only a limited number of inhibitors against enzymes of the ubiquitin system are available. I will present a fragment-based covalent ligand screening approach to identify inhibitors of thioester-forming E3 ubiquitin ligases and describe the structure-based development of an inhibitor specific for the RBR ligase HOIP.
5:05 Interactive Breakout Discussion Groups
Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Visit the conference website for discussion topics and moderators.
6:05 Welcome Reception in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)
7:10 Close of Day
Day 1 | Day 2
7:30 am Registration Open and Morning Coffee
Fragment-Based And Orthogonal Approaches
8:00 Chairperson’s Remarks
J. Brad Shotwell, PhD, Senior Principal Scientist, Tool and Lead Generation
Chemistry Group Leader, AbbVie
8:05 Fragment Screening to Assess Target Ligandability
Fredrik Edfeldt, PhD, Associate Principal Scientist, Discovery Sciences, R&D Biopharmaceuticals, AstraZeneca, Gothenburg, Sweden
Evaluating the ligandability, or chemical tractability, of a protein target is critical when defining hit-finding strategies or to prioritize amongst potential targets. Fragment screening has emerged as a useful approach for this purpose. We demonstrate that thermal shift assays can be used as a simple and generic biophysical method to assess target ligandability. We have applied the method to a set of proteins and show that the assessment is predictive for the success of HTS.
8:35 Fragment-Based Approach to Lactate Dehydrogenase A (LDHA) Inhibitors
Beth Knapp-Reed, PhD, Scientific Leader, NCE-MD Medicinal Chemistry, R&D Platform Technology & Science, GSK
A fragment-based approach was used to identify a unique series of LDHA inhibitors with good ligand efficiencies. Subsequent optimization delivered a novel lead series with LDHA cellular activity of 10 μM, selectivity against LDHB, and good physicochemical properties. The overall strategy of identifi-cation and optimization, lessons learned, and some guiding principles of the FBDD effort will be presented in the context of the discovery of a fragment-derived lead series for the inhibition of LDHA.
9:35 Coffee Break in the Exhibit Hall with Poster Viewing
10:20 Fragment-Based Discovery and Characterization of ERK1/2 Inhibitors
Puja Pathuri, PhD, Associate Director, Molecular Sciences, Astex Pharmaceuticals
Using a fragment-based campaign and multiple screening methods, including high throughput crystallography and biophysical assays, we identified and developed novel, orally bioavailable inhibitors of ERK1/2 – key components of the Ras signaling pathway in cancer cells. The inhibitors elicit a similar conformational change to currently available inhibitors but also modulate phosphorylation of ERK. Our series of pERK modulating ERK1/2 inhibitors went through progressive rounds of structure-guided optimization and iterative optimizations. The screening cascade included measurement of pRSK levels and anti-proliferative activity in ras and BRAF mutant cells.
10:50 Presentation to be Announced
11:20 Enjoy Lunch on Your Own
11:20 Conference Registration for Programs 1B-7B
PLENARY KEYNOTE PROGRAM
Click here for full abstracts.
12:20 pm Event Chairperson’s Opening Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target 2019, Cambridge Healthtech Institute
12:30 Plenary Keynote Introduction
12:40 Base Editing: Chemistry on a Target Nucleotide in the Genome of Living Cells
David R. Liu, PhD, Howard Hughes Medical Institute Investigator, Professor of Chemistry & Chemical Biology, Harvard University
1:20 PROTACs: Past, Present, and Future
Craig M. Crews, PhD, Professor, Chemistry; Pharmacology; Molecular, Cellular & Developmental Biology; Yale University
2:00 Close of Plenary Keynote Program
2:00 Dessert Break in the Exhibit Hall with Poster Viewing
2:45 Close of Lead Generation Strategies Conference