Cambridge Healthtech Instituteの第5回年次
Protein Degraders and Molecular Glues - Part 2
PLENARY KEYNOTE PROGRAM
Plenary Keynote Introduction (Sponsorship Opportunity Available)10:45 am
PLENARY: The New Science of Therapeutics
Jay E. Bradner, MD, Physician Scientist, Former President, Novartis Institutes for BioMedical Research, Inc.
I will share reflections on how new paradigms in the science of therapeutics are creating opportunities to approach historic challenges in medicine. Specifically, I will share approaches to targeting transcription factors and discuss how modularity is a paradigm for next-generation low-molecular weight and biological therapeutics. Finally, I will offer reflections on drug development and the fitness, opportunities, and challenges of the biomedical ecosystem.
PLENARY: Accelerating Drug Discovery Using Machine Learning and Cell Painting Images
Microscopy images can reveal whether a cell is diseased, is responding to a drug treatment, or whether a pathway has been disrupted by a genetic mutation. In a strategy called image-based profiling, often using the Cell Painting assay, we extract hundreds of features of cells from images. Just like transcriptional profiling, the similarities and differences in the patterns of extracted features reveal connections among diseases, drugs, and genes.
Enjoy Lunch on Your Own12:25 pm
Welcome Remarks1:45 pm
Unlocking the Power of Autophagy-Dependent Targeted Degradation
p62/SQSTM1-Dependent Targeted Autophagic Degradation of Pathological Neurodegeneration-Associated Aggregates by AUTOphagy-TArgeting Chimera (AUTOTAC)
Chang Hoon Ji, PhD, Executive Director, Bio R&D Center, Autotac Bio Co. Ltd.
Aggregates of neurodegeneration-associated hallmark proteins are causative agents of neuronal proteotoxicity, leading to progressive cell death and brain tissue deterioration. Targeted protein degradation represents an exciting and alternative approach to move beyond traditional inhibitors that have been limited to treating symptoms in neurodegeneration, and fundamentally eliminate the causative pathological agents. The AUTOphagy-TArgeting Chimera (AUTOTAC) TPD platform was used to selectively degrade pathological aggregates, and combat neurodegeneration-associated pathophysiology.
Michael Drummond, PhD, Scientific Applications Manager, Chemical Computing Group
Among targeted protein degradation approaches, molecular glues have emerged as especially promising, due to their smaller size and druglike properties. However, to date, rational discovery of molecular glues has proven difficult. In this work, we will discuss multiple computational techniques for modeling ternary complexes containing glues. The most effective models result from considering molecular glues as “linkerless bifunctionals.” Recent work in prioritizing prospective glue designs based on predicted degradation efficacy will also be presented.
Refreshment Break in the Exhibit Hall with Poster Viewing3:25 pm
CoraFluors-Enabled Assays for Comprehensive and Quantitative Characterization of Molecular Degraders and Transcriptional Regulators
Ralph Mazitschek, PhD, Assistant Professor, Harvard Medical School; Co-Director of the Chemical Biology Platform, Center for Systems Biology, Massachusetts General Hospital
Progress and success in drug discovery are highly dependent on the availability of robust and quantitative assays that allow for the straightforward and reliable characterization of molecular interactions and target abundance. We have developed novel CoraFluor-based TR-FRET assay approaches that overcome existing limitations and facilitate the accurate profiling of molecular degraders and transcriptional regulators, including the facile quantification of endogenous protein levels, target affinity measurements, and characterization of ternary complexes.
Bifunctional Degradation Activating Compounds (or BiDAC Degraders): Brain Exposure and Correlation to Pharmacodynamic Effect
Ritu Singh, PhD, Associate Director, DMPK, C4 Therapeutics Inc.
An important step in the development of drugs targeted for central nervous system activity involves the accurate determination of the extent of drug exposure to the brain. We have recently evaluated the TRANSIL Brain Absorption assay, a high-throughput matrix-free method that measures the affinity of drugs to porcine brain membranes to estimate their binding to brain tissue and have correlated the unbound brain exposure to pharmacodynamic (PD) effect.
Dinner Short Course Registration*5:00 pm
*Premium Pricing or separate registration required. See Short Courses page for details.
Close of Day8:00 pm
Registration and Morning Coffee7:30 am
NOVEL DEGRADERS FOR ONCOLOGY TARGETS
Discovery of KT-474 (SAR444656) - A Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases
Yi Zhang, PhD, Director, Medicinal Chemistry, Kymera Therapeutics
Blocking the signaling activity of Interleukin-1 receptor associated kinase 4 (IRAK4) represents an attractive target for the treatment of autoimmune diseases. The signaling activity of IRAK4 is dependent both on its kinase activity and scaffolding functions, and thus degradation of IRAK4 represents a potentially superior approach to kinase inhibition. This presentation will detail the efforts that led to the identification of potent, selective and orally bioavailable degraders of IRAK4. Included will be a discussion of the computational tools and approaches utilized for the discovery of KT-474 (SAR444656), a heterobifunctional degrader of IRAK4 that is currently entering Phase II clinical trials for the treatment of atopic dermatitis (AD) and hidradenitis suppurativa (HS).
Discovery and Development of ORM-6151 - A First-in-Class TPD2 CD33-Targeted GSPT1 Degrader for Treatment of AML
James Palacino, PhD, Vice President, Biology, Orum Therapeutics
AML is a malignancy with limited treatment options and poor prognosis. CD33 represents a good target, with high expression in most AML blasts. Small-molecule GSPT1 degraders drive clinical response in AML patients, with tolerability challenges. We designed a CD33-targeted ADC with a GSPT1 degrader. ORM-6151 demonstrated robust activity against many AML models with high tolerability in healthy progenitors. ORM-6151 represents a novel therapeutic approach for the treatment of AML.
Discovery of a Rationally Designed Potent and Selective CK1a Degrader Active against a Broad Range of Human Cancer Cell Lines
Gisele Nishiguchi, PhD, Group Leader, St. Jude Children's Research Hospital
By phenotypic screening St. Jude’s proprietary molecular glue library across a range of pediatric cancer cell lines, we identified several degraders of CK1a. Through structure-guided optimization, we developed SJ3149, a potent and selective CK1a degrader. The crystal structure of the CK1a+CRBN+DDB1+SJ3149 complex provided rationale for the improved degradation via direct contacts between SJ3149 and CK1a. In a panel of 115 human cancer cell lines, SJ3149 displayed broad anti-proliferative activity.
Discovery of Next-Generation Small Molecule Protein Degraders for Oncology
Simon Bailey, PhD, MBA, Executive Vice President & Head of Drug Discovery, Plexium, Inc.
Targeted protein degradation (TPD) is a clinically-validated drug modality. However, it is recognized that PROTACs and cereblon molecular glues have limitations and much of the therapeutic potential of TPD remains to be unlocked. This talk will focus on Plexium's approach to identifying next-generation monovalent protein degraders of important targets for oncology and expanding the toolbox of E3 ligases that can be developed into molecular glues.
In-Person Group Discussions10:05 am
Coffee Break in the Exhibit Hall with Poster Viewing10:50 am
Discovery and Development of the First-in-Class Platelet-Sparing BCL-XL PROTAC Degrader, and beyond
Sajid Khan, PhD, Assistant Professor/Research, Biochemistry & Structural Biology, University of Texas Health San Antonio
BCL-XL is a well-validated cancer target. However, the on-target and dose-limiting platelet toxicity induced by BCL-XL inhibition prevents the clinical use of BCL-XL inhibitors. In my presentation, firstly I will cover the discovery and development of the first-in-class platelet-sparing and tumor-selective BCL-XL degrader DT2216. Next, I will share our recent preclinical data where we are using DT2216 in combination with different chemo- and targeted drugs with a goal of preventing resistance and developing safe and effective therapies.
Discovery of the First Degrader of Membrane Protein IRE1a and Mutation-Resistant Catalytic EML4-ALK Degraders
Yingpeng Liu, PhD, Scientist II, Center for Protein Degradation, Dana Farber Cancer Institute
PROTACs have generated considerable interest in drug discovery because of their potential to target so-called undruggable proteins. This talk will demonstrate our work using PROTACs as chemical probes for validating the degradation of the endoplasmic reticulum (ER) stress sensor IRE1α, which led to the development of the first degrader of the protein, as well as our discovery of catalytic degraders that effectively address kinase site mutations in EML4-ALK oncogenic fusions.
Sponsored Presentation (Opportunity Available)12:30 pm
Transition to Lunch1:00 pm
Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:05 pm
Dessert Break in the Exhibit Hall with Last Chance for Poster Viewing1:35 pm
DEGRADING ONCOGENIC TRANSCRIPTION FACTORS
Understanding the Recruitment of Zinc-Finger-Based Transcription Factors to Cereblon in the Presence of Molecular Glues
Charles Wartchow, PhD, Associate Director, Global Discovery Chemistry, Novartis Institutes for BioMedical Research
Transcription factors are known to bind to cereblon in the presence of molecular glues and some reports implicate interactions with multiple zinc fingers. We present biophysical and structural assessments of the minimal binding domains of IKZF2 and another transcription factor revealing that two zinc fingers interact with cereblon:glue complexes. In these examples, the binding modes are distinct and may have implications for the design of selective degraders.
Discovery and Characterization of an IKZF2 Selective Molecular Glue Degrader with Best-in-Class Potential
Helai Mohammad, PhD, Vice President & Head, Biology, Proteovant Therapeutics
IKZF2 (Helios) plays an important role in maintaining stability and function of regulatory T cells (Tregs). Proteovant applied a structure-guided drug discovery approach to identify an IKZF2 selective molecular glue degrader, PVTX-405. PVTX-405 shows selective degradation of IKZF2 in vitro and in vivo. PVTX-405 treatment reduces suppressive activity of human Treg cells ex vivo and delays growth of MC38 tumors in immune competent mice in vivo.
New Technologies for Advancing the Targeted Protein Degradation
H. Umit Kaniskan, PhD, Associate Professor, Laboratory of Dr. Jian Jin, Department of Pharmacological Sciences, Icahn School of Medicine at Mt. Sinai
The Jian Jin Laboratory at Mount Sinai is a leader in discovering novel degraders targeting oncogenic proteins and developing new technologies for advancing the targeted protein degradation field. Our lab’s recent progress advancing the targeted protein degradation, including TF-PROTAC, Bridged PROTAC, Folate-caged PROTAC, opto-PROTAC, and KEAP1-recruiting PROTAC technologies will be presented.
Targeted Degradation of STAT Proteins
Longchuan Bai, PhD, Associate Research Scientist, Laboratory of Dr. Shaomeng Wang, University of Michigan
STAT (signal transducer and activator of transcription) proteins are a family of transcription factors that mediate signal transduction downstream of cytokine and growth factor receptors. Hyperactivation of STAT3 and STAT5 has been linked to cancer cell proliferation, survival, stemness, and immune evasion, making them attractive targets for cancer therapy. STATs have been difficult to target by traditional small-molecule inhibitors. Employing the PROTAC technology, we have developed highly selective and potent STAT3 or STAT5 degraders with strong anti-tumor activities in hematologic cancer models.
Close of Conference4:20 pm