Cambridge Healthtech Instituteの第6回年次会議
Protein Degraders & Molecular Glues - Part 2
（タンパク質分解誘導剤・分子接着剤 - パート2）
2023年4月12 - 13日
Registration Open12:00 pm
Dessert Break in the Exhibit Hall with Poster Viewing12:45 pm
Welcome Remarks1:30 pm
ADVANCING MOLECULAR GLUES
Expansion of the Druggable Genome through Rational Approaches to Molecular Glue Discovery
Molecular glue degraders offer to significantly expand the druggable genome through their ability to target proteins with no ligand binding sites. Thalidomide analogs offer a case-study in molecular glue mechanisms, with the discovery of neosubstrate degrons enabling prospective searches for on- and off-target activities. Structure-based approaches to molecular glue drug discovery show promise for the rational identification and optimization of novel glue systems, generating a unique and differentiated target space.
Novel Monovalent Protein Degraders and Molecular Glues in Cancer Drug Discovery
This talk will discuss Plexium's latest approaches to discovering novel molecular glues and monovalent degraders of therapeutically important cancer targets. It will highlight Plexium's unique approach and capabilities to discover monovalent degraders and expand the E3 ligase toolbox.
Sponsored Presentation (Opportunity Available)2:40 pm
Refreshment Break in the Exhibit Hall with Poster Viewing3:10 pm
Discovery of Novel CK1a-Selective Molecular Glue Degraders Demonstrating Strong Anti-Tumor Activity
CK1a, an isoform of casein kinase 1 (CK1), promotes tumor growth by increasing the negative effects of MDM2 and MDMX on p53. This presentation will discuss our efforts to identify cereblon (CRBN) E3 ligase-mediated CK1a-selective molecular glue degraders, which demonstrated good PK properties and robust pharmacological activities in various preclinical models of AML.
FEATURED PRESENTATION: Using Covalent Chemoproteomic Platforms to Enable Targeted Protein Degradation
The Nomura Research Group is focused on reimagining druggability using chemoproteomic platforms to develop transformative medicines. Our first major focus is on developing and applying chemoproteomics-enabled covalent ligand discovery approaches to rapidly discover small-molecule therapeutic leads that target unique and novel ligandable hotspots for undruggable protein targets and pathways. Our second research area focuses on using chemoproteomic platforms to expand the scope of targeted protein degradation technologies. This talk will focus on using covalent chemoproteomic strategies for developing next-generation strategies for targeted protein degradation applications using both heterobifunctional and molecular glue-based strategies.
In-Person Group Discussions5:00 pm
Exploring Innovative Approaches for Developing Molecular Glues
- Structure-based approaches to molecular glue drug discovery
- Expanding the E3 ligase toolbox
- Covalent chemoproteomic strategies for developing next-gen degraders
Close of Day5:45 pm
Registration Open7:15 am
Diversity in Chemistry Breakfast Discussion (Sponsorship Opportunity Available)7:45 am
Diversity in Chemistry beyond Molecules: Gender and More
We encourage all to attend this moderated, audience-interactive discussion session. When it comes to increasing diversity among scientists, there continues to be a drop-off as one moves higher in leadership. Where do systemic challenges remain, what is your experience, and how can we continue to equalize the system?
Topics may include below, but will be guided by audience input:
- Where does the 'drop-off' of women in the chemistry career progression pipeline occur and why?
- How did the pandemic and other sea changes in the past three years bring us closer to or further from equality?
- What issues arose that you thought were solved?
- Diversity in life paths should include us all - how are men and nonbinary scientists being included?
- Intersectionality and equality - what is the experience of women of color, first-generation women scientists, and others?
PLENARY KEYNOTE SESSION
Plenary Keynote Introduction (Sponsorship Opportunity Available)8:35 am
Reflections on a Career as a Medicinal Chemist in Drug Discovery
A successful drug candidate depends on many factors: creativity of scientists involved, effective collaboration and commitment by the team, and the quality of the compound advanced. I reflect on a 40-year career pursuing the discovery of drug candidates designed to address unmet medical need in the cardiovascular, CNS, and viral diseases therapeutic areas and share undervalued strategies and other synthetic chemistry approaches for overcoming specific medicinal chemistry challenges.
Coffee Break in the Exhibit Hall with Poster Viewing9:30 am
PLATFORMS ENABLING DEGRADER DEVELOPMENT
Enabling Technologies to Determine Absolute Protein Abundance and Degradation Kinetics for PROTACs
Proteolysis-targeting chimera (PROTAC) is a frequently used approach for targeted protein degradation. In this talk, we’ll present development and application of high throughput technologies to quantitatively measure absolute protein abundance for target protein and E3 ligases, and determine degradation kinetics of PROTACs in cells. Case studies will be included to demonstrate their impact on compound profiling and differentiation for PROTAC projects.
Molecular Glues for Protein Degradation and Beyond
Small molecules that induce protein degradation through ligase-mediated ubiquitination, are showing considerable promise as a new pharmacological modality. Following clinical proof of concept by thalidomide and related IMiDs, several new molecular entities are entering clinical development. Significant progress has been made towards chemically induced targeted protein degradation using heterobifunctional small molecule ligands and exciting opportunities arise from better understanding molecular glues. We will present recent work towards a better understanding of the molecular principles that govern neo-substrate recruitment by small molecule degraders.
DEL is an ideal method for finding potent, specific POI binders, especially for challenging targets. DEL technology allows systematic investigation E3 ligase family proteins. HitGen TPD platform toolboxes for degrader discovery and optimization.
Enabling Platforms to Accelerate the Development of Degraders for Intracellular and Extracellular Proteins
I will present our recent progresses for the development of degraders for both intracellular and extracellular proteins. For the former, I will focus on the development of rapid synthesis of PRTAC (Rapid-TAC) platforms. For the latter, I will focus on the development of degraders that recruit different lysosome targeting receptors.
A Chemical Biology Toolbox for Characterizing Novel Protein Degraders
Targeted protein degradation by small molecules have shown consolidated promise as a new pharmacological approach. We give an overview of our lead generation cascades for the protein degradation modality with focus on proteomics strategies to define degraders selectivity and mechanism of actions. We discuss assay toolboxes and future direction of unbiased discovery of emerging molecular glue degraders and relationship between target and ligase to inform design.
Transition to Lunch12:40 pm
In recent years, targeted protein degradation has emerged as a new modality to control protein levels in vivo. Both bifunctional degraders, such as PROTACs, and monovalent degraders, such as molecular glues, can be developed to selectively and catalytically target a protein-of-interest for degradation. Despite the many advantages of these approaches, numerous challenges still exist in the development of degraders, particularly concerning the rational design of efficacious molecules. This talk will explore the most promising methodologies we have developed to evaluate putative degrader designs. Recent case studies will be presented, demonstrating in particular the utility of these approaches on larger scale degrader investigations. Particular focus will be given to the quality of the predictions as a function of available input knowledge, such as using hydrogen-deuterium exchange (HDX) data to inform protein-protein interface prediction and, ultimately, ternary complex geometry.
Refreshment Break in the Exhibit Hall with Poster Awards Announced1:20 pm
Poster Award (Sponsorship Opportunity Available)
OPTIMIZING DRUG-LIKE PROPERTIES
Developing Alternative Warheads for CRBN-Directing PROTACs
This talk will describe the design, SAR and in vitro/vivo properties of Phenyl Glutarimide (PG) and Phenyl Dihydrouracil (PD) ligands, and corresponding BET, JAK and LCK PROTACs. Comparative studies with corresponding IMiD PROTACs, and screening efforts for alternative CRBN binders will also be discussed.
Targeted Protein Degradation of RET Kinase as a Strategy to Achieve Pan-Mutant and Pan-Fusion Anti-Cancer Activity
Activating point mutations and chromosomal fusions of the Rearranged During Transfection (RET) receptor tyrosine kinase drive numerous human cancers. Here we describe the medicinal chemistry efforts leading to the orally bioavailable, pan-mutant, and pan-fusion RET heterobifunctional degrader, compound 9. In vitro, compound 9 promotes potent degradation of the wild-type and mutant RET kinase domains. In vivo, oral dosing of compound 9 in xenograft models of RET-driven cancers leads to robust tumor regression.
ORM-5029: A First-in-Class, Tumor-Targeted, Targeted Protein Degradation Therapy for HER2-Positive Breast Cancer
While targeted protein degradation therapies hold much promise, the challenges of achieving the right balance of potency, exposure, and tolerability represent hurdles to development. Herein we present the rationale, implementation, and progression of first-in-class, dual precision targeted protein degrader (TPD2). We developed a proprietary class of GSPT1 degrader molecules and paired them with a Her2 targeting antibody, then we profiled these conjugates for the desired therapeutic profile. Our first clinical GSPT1 TPD2 conjugate; ORM-5029 demonstrated superior in vitro and in vivo potency as compared to other known small molecule GSPT1 degraders as well as other ADC's in Her2 models including those with low-Her2 settings.
Networking Refreshment Break3:35 pm
Bifunctional Degradation Activating Compounds - Overcoming ADME Challenges
Targeted Protein Degradation has the potential to transform the treatment of disease. C4T’s TORPEDO platform enables the design of potent, selective, and orally available targeted protein degraders including monofunctional or MonoDAC degraders and heterobifunctional or BiDAC degraders and has delivered a robust pipeline of preclinical candidates. The presentation will discuss in vitro and in vivo strategies and challenges in the context of degrader drug discovery. As a case study, preclinical ADME properties of CFT8634, a potent, selective, and orally available BiDAC degrader of BRD9 for the treatment of SMARCB1-perturbed cancers will be discussed.
Direct-to-Biology Accelerates PROTAC Synthesis and the Evaluation of Linker Effects on Permeability and Degradation
A platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) has been developed using a direct-to-biology (D2B) approach focusing on linker effects. A large number of linker analogs, with varying length, polarity, and rigidity, were rapidly prepared and, without chromatographic purification, characterized in four cell-based assays by streamlining time-consuming steps in synthesis and purification. The expansive dataset informs on linker structure-activity relationships (SAR) for in-cell E3 ligase target engagement, degradation, permeability, and cell toxicity.
In cellulo PROTAC Assembly from Reversibly Interacting Components
A significant drawback of PROTACs is their large size, which will likely limit bioavailability, especially to the CNS and in solid tumors. Here we show that rapidly reversible bio orthogonal reactions can be employed to assemble active PROTACs inside of cells from their component target protein and E3 Ub ligase ligands. These much smaller pieces may exhibit superior bioavailability and in vivo efficacy for some applications.
Discovery of FHD-609: A Potent and Selective Heterobifunctional Degrader of BRD9
Synovial sarcoma is a rare, often aggressive malignancy with limited therapeutic options. In preclinical studies, FHD-609 has been shown to selectively degrade bromodomain-containing protein 9 (BRD9), taking advantage of a synthetic lethal relationship with the SS18-SSX translocation. The discovery and optimization of this first-in-class clinical compound will be described.
Close of Conference5:55 pm