Degrader Digest - Issue 2

Last updated April 22, 2021. Dear Protein Degradation Friends, In this issue, we highlight new companies in the space, additional biology animations, and an updated list of industry events. We also include new media articles and scientific papers. You can also access Issue 1. We are focusing each issue on new information so you can quickly stay informed without having to remember what you read in previous issues. A number of readers have requested push notifications. This issue includes a web form to submit your email, which will only be used for informing you of new issues. We have also received positive comments on the video animations. I am personally a huge fan of animations to illustrate complex biological processes. If you have good animations you would like to share, please submit them to degraderdigest@gmail.com. In a future issue, we would like to include short interview videos highlighting exciting TPD research. If you would like to present your work, please email us an abstract describing your research. Many thanks! -Marc Cover art: proteasome illustration

Degrader Digest - Issue 2

Media

Presentations

  • Deshaies (Amgen) 1: A primer on the ubiquitin-proteasome system

    https://www.ibiology.org/cell-biology/primer-ubiquitin-proteasome-system/ Part 1: A primer on the ubiquitin-proteasome system: The ubiquitin-proteasome system is one of the principal means of degrading misfolded, mutated, or unwanted proteins in the cell. Part 2: Cullin-RING ubiquitin ligases: Over 200 types of cullin-RING ubiquitin ligases are formed by interchanging subunits. This carefully regulated system allows for great substrate specificity. Part 3: Targeting the ubiquitin-proteasome system in cancer: The ubiquitin-proteasome system is overworked in mutation-ridden cancer cells making it a potential target for anti-cancer drugs. https://www.ibiology.org/ibioseminars/cell-biology/primer-ubiquitin-proteasome-system.html Talk Overview: Neurons, blood cells and muscle cells have distinct morphologies and functions because they have different proteomes or collections of proteins. The proteome is maintained through the synthesis and degradation of different proteins. In his first talk, Dr. Deshaies explains that the ubiquitin-proteasome system (UPS) is the principal means of degrading proteins in the cytosol and therefore is key to maintaining the proteome. Ubiquitin is a small protein that can be added to, or removed from, other proteins altering their function or targeting them for degradation. Deshaies describes the multiple mechanisms for regulating ubiquitin ligase activity and the importance of protein degradation in many cell signaling pathways and in the removal of defective proteins. In Part 2, Deshaies delves more deeply into a specific group of ubiquitin ligases, the cullin-RING ligases (CRLs). By rearranging the subunits of CRLs in a combinatorial process, it is possible to generate more than 200 of these enzymes each with a specific substrate. The formation and activity of CRL complexes in the cell is regulated by the conjugation/deconjugation (Nedd8) or binding/dissociation (Cand1) of other proteins to the CRL complex, and this, in turn, is influenced by the binding of substrate to CRL. This carefully regulated mechanism allows cells to match the level and specificity of ubiquitin ligation to the level of particular substrates in the cell. In many types of cancer, cells have a very high rate of mutation. These mutated proteins are frequently less stable than normal proteins and need to be degraded by the UPS. In addition, cancer cells are often aneuploid leading to the overexpression of certain proteins. These extra proteins also need to be degraded by the UPS. In both cases, the UPS in cancer cells is overworked. This suggests that cancer cells should be less able to tolerate inhibition of the UPS than normal cells. In his last talk, Deshaies describes strategies to develop cancer drugs based on inhibition of the UPS. Speaker Biography: At the time that this video was recorded, Dr. Raymond Deshaies was a Professor of Biology at the California Institute of Technology and an Investigator of the Howard Hughes Medical Institute. Deshaies will be transitioning to a new position as Senior Vice President for Discovery Research at Amgen, in 2017. Deshaies received his BS in biochemistry from Cornell University and his PhD, also in biochemistry, from the University of California, Berkeley. It was as a post-doctoral fellow at the University of California, San Francisco, that Deshaies found that a cell cycle protein he was investigating was modified by the addition of ubiquitin. This began a career-long interest in the role of the ubiquitin-proteasome system in regulating protein homeostasis, both in normal cell function and in diseases such as cancer. Deshaies has received numerous awards for his outstanding research. He has been elected as a Fellow of the American Association for the Advancement of Science (2007), as a Member of the American Academy of Arts and Sciences (2011) and as a Member of the US National Academy of Sciences (2016). Learn more about Deshaies’ research here: http://www.deshaieslab.com/ray-deshaies.html

  • New Frontiers in Targeted Protein Degradation and Degrader Development

    Learn More about Targeted Protein Degradation: https://www.tocris.com/product-type/targeted-protein-degradation The use of heterobifunctional small molecule Degraders (e.g. PROTACs, SNIPERs etc) to elicit targeted protein degradation (TPD) is an area of increasing interest in chemical biology. They offer an attractive approach for inducing selective protein knockdown in a reversible and tuneable manner, without requiring genetic modification of cells. This is currently an area of tremendous interest, offering a potential new approach to tackle the ‘undruggable’ proteome and overcome common resistance mechanisms to current therapies. This webinar provides an introduction to Targeted Protein Degradation, discussing design and optimization of Degrader molecules and how structural biology and rational design can shed light on the Degrader development process. The second section of the webinar will present the dTAG platform for target validation. dTAG molecules specifically recognize and degrade FKBP12F36V fusion proteins, presenting a new platform for target validation studies.

Private Companies

Working on Protein Degradation Candidates

  • ****NEW: Dunad Therapeutics

    Dunad Therapeutics is focusing on the development of next-generation targeted protein degradation therapies. Dunad’s platform enables selective degradation via direct target modification using tuneable mono-valent small molecules, unlocking new target space and allowing for the development of more drug-like, orally bioavailable and CNS-accessible protein degraders.

  • A-Alpha Bio | Measure more protein interactions

    AlphaSeq is a synthetic biology platform used to accelerate drug development by enabling library-on-library measurements of protein interactions Discover biologics with defined specificity to many targets Optimize affinity and specificity rapidly in one workflow Characterize library binding to many targets simultaneously What can you do with AlphaSeq? Discover, optimize, and characterize biologics Screen antagonists against full interaction networks Screen agonists in a flexible library format Learn about opportunities to partner with A-Alpha Bio

  • Amphista Therapeutics

    Amphista Therapeutics is developing medicines for hard to treat diseases using next generation targeted protein degradation approaches. Our portfolio uses our own novel protein degrading mechanisms which build on the strengths of current protein degradation approaches whilst directly addressing their limitations. or why not drop us an email info@amphista.com Amphista Therapeutics is an exciting spin out company founded by Advent Life Sciences and built on groundbreaking science from the laboratory of Professor Alessio Ciulli (University of Dundee), a world leader in the field of targeted protein degradation.

  • BioTheryX

    We are a clinical-stage company harnessing our deep expertise in Targeted Protein Degradation to restore protein homeostasis in order to treat a wide range of diseases.

  • Captor Therapeutics

    Captor Therapeutics is a high-tech pharmaceutical company focused on targeting the undruggable proteome.

  • Cedilla Therapeutics

    Cedilla is harnessing intrinsic protein stability mechanisms to broaden the reach of small molecule therapeutics. We work on cancer and other diseases caused by protein dysregulation.

  • Civetta Therapeutics

    Civetta Therapeutics was founded to advance new medicines through small molecule targeting of propeller domains with the goal of developing important therapeutics for cancers and other diseases.

  • Coho Therapeutics

    Coho Therapeutics is a nascent biotechnology company developing medicines within a new class of therapeutics called protein degraders.

  • Cullgen

    Cullgen is a privately held biopharmaceutical company dedicated to the development of first-in-class new chemical entities (NCEs) for the treatment of diseases lacking effective therapeutic approaches.

  • Dialectic Therapeutics

    Dialectic Therapeutics (DT) is a pre-clinical biotechnology company dedicated to the development of unique, impactful anti-cancer drugs that effectively treat patients with few to no other options.

  • FIMECS, Inc.

    FIMECS is a protein degradation technology-based drug discovery biotech focused on developing first-in-class protein degradation therapeutics for cancers and other difficult-to-treat diseases.

  • Frontier Medicines

    Frontier Medicines’ integrated approach leverages chemoproteomics and machine learning to accelerate the development of medicines that drug the “undruggable” protein targets that drive human disease.

  • Hinova Pharmaceuticals

    Hinova Pharmaceuticals Inc. is a high-tech innovative drug discovery and development company dedicated to bring new medicines to patients worldwide.

  • Lycia Therapeutics

    Developing first-in-class therapeutics that degrade extracellular proteins to address difficult-to-treat diseases

  • Monte Rosa Therapeutics

    Our drug discovery platform is tailored to promote specific protein ubiquitination and subsequent proteasomal degradation of disease-causing, undruggable proteins, in essence leading to pharmacological protein knockout with high efficiency and accuracy.

  • Neomorph

    Advancing the science of targeted protein degradation to destroy ‘undruggable’ proteins and cure disease.

  • Orionis Biosciences

    Orionis Biosciences is a life sciences company pioneering technological innovation in genome-scale drug discovery and tunable molecular design of novel therapeutic drug modalities.

  • PhoreMost

    PhoreMost’s SITESEEKER® platform enables the inception of First-in-class drug discovery programmes. Using this unique approach, PhoreMost is developing an internal asset pipeline in oncology and other diseases of ageing.

  • Pin Therapeutics

    Pin Therapeutics aims to develop targeted protein degradation hijacking ubiquitin and/or UBL (ubiquitin-like) biology.

  • Plexium | A Comprehensive Drug Development Methodology

    At Plexium, our mission is to reinvent the way medicines are discovered. We are implementing novel technologies and clinical approaches that enable the rapid and scalable development of first-in-class therapeutics. Funds will help advance Plexium’s DELPhe platform to discover novel E3 ligase-modulating therapeutics to treat cancer... Plexium CEO Swamy Vijayan to present at the North American Protein Degradation Congress in San Diego, CA on February... Plexium CEO Swamy Vijayan to present at the Targeted Protein Degradation Summit in Boston on October 23, 2019.

  • PolyProx Therapeutics - PolyProx - focused on the discovery and development of a new class of drugs to treat cancer and neurodegenerative diseases

    PolyProx Therapeutics is a biotechnology company focused on the discovery and development of a new class of drugs, Polyproxin® molecules, to treat cancer and neurodegenerative diseases.

  • Progenra

    Progenra is Dedicated to Finding New Medicines Through Targeting the Ubiquitin Proteasome System to fill unmet needs in a spectrum of therapeutic areas.

  • Proxygen

    Proxygen develops therapies against cancer and other life-threatening diseases by reprogramming the cellular protein quality control system through particular drugs called “molecular glue degraders”.

  • Roivant Sciences

    Roivant Sciences is a biopharmaceutical company focused on realizing the full value of promising drug candidates to improve the lives of patients.

  • Sitryx

    Sitryx is a biopharmaceutical company focused on regulating cell metabolism to develop first-in-class disease modifying therapeutics in immuno-oncology and immuno-inflammation.

  • Trilo Therapeutics

    Trilo Therapeutics is focused on the discovery of novel inhibitors of protein-protein interactions for therapeutic purposes.

  • Ubix Therapeutics

    Ubix Therapeutics, Inc. develops novel anti-cancer drugs based on Degraducer, target protein degradation platform technology.

  • Vividion Therapeutics

    Vividion Therapeutics is transforming the future of human health through the creation of highly selective small molecule medicines that drug traditionally inaccessible targets.

Public Companies

Working on Protein Degradation Candidates

  • C4 Therapeutics

    C4 Therapeutics® is committed to transforming the treatment of cancer, neurological, and other important diseases with novel early stage therapies that eliminate disease-causing proteins. Our approach to medicine harnesses the innate machinery of the cell to attack disease and potentially bring deep and durable responses to patients.

  • Kymera

    Kymera is a biopharmaceutical company developing novel protein degrader therapeutics to treat disease in powerful new ways, which harness the body’s natural protein degradation system to selectively degrade disease causing proteins with the goal of completely removing them from the body. Kymera is driven to invent transformative medicines for a wide variety of diseases where traditional drug modalities have failed to sufficiently unlock the appropriate biological solution.

  • Nurix Therapeutics

    Nurix Therapeutics discovers drugs that harness the body’s natural process to control protein levels. Our drugs control ubiquitin E3 ligases, the key enzymes responsible for protein breakdown in human cells, as a unique therapeutic approach called targeted protein modulation to treat a broad range of diseases. Our focus is on developing targeted therapies to treat cancer including novel, small molecule immuno-oncology agents.

  • Arvinas | Inspiring a New Pharmaceutical Paradigm

    Arvinas is a pharmaceutical company focused on developing new small molecule strategies aimed at degrading disease-causing cellular proteins. We are translating these innovative protein degradation approaches into novel drugs for the treatment of cancer and other diseases.

Scientific Papers

  • Identification and selectivity profiling of small-molecule degraders via multi-omics approaches

    April 2, 2021 Natalie S. Scholes, Cristina Mayor-Ruiz, Georg E. Winter The therapeutic modality of targeted protein degradation promises to overcome limitations of traditional pharmacology. Small-molecule degraders recruit disease-causing proteins to E3 ubiquitin ligases, prompting their ubiquitination and degradation by the proteasome. The discovery, mechanistic elucidation, and selectivity profiling of novel degraders are often conducted in cellular systems. This highlights the need for unbiased multi-omics strategies that inform on the functionally involved components. Here, we review how proteomics and functional genomics can be integrated to identify and mechanistically understand degraders, their target selectivity as well as putative resistance mechanisms.

  • Transforming targeted cancer therapy with PROTACs: A forward-looking perspective

    April 2021 William Farnaby, Manfred Koegl, Darryl B. McConnell, Alessio Ciulli Small-molecule targeted protein degraders have in recent years made a great impact on the strategies of many industry and academic cancer research endeavours. We seek here to provide a concise perspective on the opportunities and challenges that lie ahead for bifunctional degrader molecules, so-called ‘Proteolysis Targeting Chimeras (PROTACs),’ in the context of cancer therapy. We highlight high-profile studies that support the potential for PROTAC approaches to broaden drug target scope, address drug resistance, enhance target selectivity and provide tissue specificity, but also assess where the modality is yet to fully deliver in these contexts. Future opportunities presented by the unique bifunctional nature of these molecules are also discussed.

  • Development of Triantennary N-Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins

    March 24, 2021 Yaxian Zhou, Peng Teng, Nathan T. Montgomery, Xiaolei Li, and Weiping Tang Targeted protein degradation (TPD) technology has drawn significant attention from researchers in both academia and industry. It is rapidly evolved as a new therapeutic modality and also a useful chemical tool in selectively depleting various protein targets. As most efforts focus on cytosolic proteins using PROteolysis TArgeting Chimera (PROTAC), LYsosome TArgeting Chimera (LYTAC) recently emerged as a promising technology to deliver extracellular protein targets to lysosome for degradation through the cation-independent mannose-6-phosphate receptor (CI-M6PR). In this study, we exploited the potential of the asialoglycoprotein receptor (ASGPR), a lysosomal targeting receptor specifically expressed on liver cells, for the degradation of extracellular proteins including membrane proteins. The ligand of ASGPR, triantennary N-acetylgalactosamine (tri-GalNAc), was conjugated to biotin, antibodies, or fragments of antibodies to generate a new class of degraders. We demonstrated that the extracellular protein targets could be successfully internalized and delivered into lysosome for degradation in liver cell lines specifically by these degraders. This work will add a new dimension to TPD with cell type specificity.

  • The role of reversible and irreversible covalent chemistry in targeted protein degradation

    March 30, 2021 Hannah Kiely-Collins, Georg E. Winter, Gonçalo J.L. Bernardes Proteolysis-targeting chimeras (PROTACs) that degrade disease-causing proteins by hijacking the endogenous ubiquitin-proteasome system have emerged as an exciting and transformative technology in both chemical biology and drug discovery. Currently, the majority of PROTACs use reversible non-covalent ligands for both the target protein of interest (POI) and E3 ligase. In this review, we explore the burgeoning role of reversible and irreversible covalent chemistry in targeted protein degradation. We highlight the key advantages of targeted covalent inhibitors, whether as the target POI or E3 ligase ligand, such as their ability to enhance the selectivity of PROTACs, enable access to more of the “undruggable” proteome and expand the repertoire of recruited E3 ligases.

  • DCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras

    March 30, 2021 Xiaoyu Zhang, Lena M. Luukkonen, Christie L. Eissler, Vincent M. Crowley, Yu Yamashita, Michael A. Schafroth, Shota Kikuchi, David S. Weinstein, Kent T. Symons, Brian E. Nordin, Joe L. Rodriguez, Thomas G. Wucherpfennig, Ludwig G. Bauer, Melissa M. Dix, Dean Stamos, Todd M. Kinsella, Gabriel M. Simon, Kristen A. Baltgalvis, and Benjamin F. Cravatt Ligand-induced protein degradation has emerged as a compelling approach to promote the targeted elimination of proteins from cells by directing these proteins to the ubiquitin-proteasome machinery. So far, only a limited number of E3 ligases have been found to support ligand-induced protein degradation, reflecting a dearth of E3-binding compounds for proteolysis-targeting chimera (PROTAC) design. Here, we describe a functional screening strategy performed with a focused library of candidate electrophilic PROTACs to discover bifunctional compounds that degrade proteins in human cells by covalently engaging E3 ligases. Mechanistic studies revealed that the electrophilic PROTACs act through modifying specific cysteines in DCAF11, a poorly characterized E3 ligase substrate adaptor. We further show that DCAF11-directed electrophilic PROTACs can degrade multiple endogenous proteins, including FBKP12 and the androgen receptor, in human prostate cancer cells. Our findings designate DCAF11 as an E3 ligase capable of supporting ligand-induced protein degradation via electrophilic PROTACs.

  • A Method for Determining the Kinetics of Small-Molecule-Induced Ubiquitination

    March 29, 2021 Ellen F. Vieux, Roman V. Agafonov, Lydia Emerson, Marta Isasa, Richard W. Deibler, Jeffrey R. Simard, David Cocozziello, Brendon Ladd, Linda Lee, Heng Li, Stephen Archer, Mark Fitzgerald, Ryan Michael, Christopher G. Nasveschuk, Eunice S. Park, Gunther Kern, David A. Proia, Andrew J. Phillips, and Stewart L. Fisher Recent advances in targeted protein degradation have enabled chemical hijacking of the ubiquitin–proteasome system to treat disease. The catalytic rate of cereblon (CRBN)-dependent bifunctional degradation activating compounds (BiDAC), which recruit CRBN to a chosen target protein, resulting in its ubiquitination and proteasomal degradation, is an important parameter to consider during the drug discovery process. In this work, an in vitro system was developed to measure the kinetics of BRD4 bromodomain 1 (BD1) ubiquitination by fitting an essential activator kinetic model to these data. The affinities between BiDACs, BD1, and CRBN in the binary complex, ternary complex, and full ubiquitination complex were characterized. Together, this work provides a new tool for understanding and optimizing the catalytic and thermodynamic properties of BiDACs.

  • SLAS Discovery Special Issue: Advances in Protein Degradation

    Volume 26 Issue 4, April 2021

  • Protein Polymerization as a Novel Targeted Protein Degradation Mechanism

    March 24, 2021 Berger, Raphaëlle, and Anthony W. Partridge Traditionally, biomedical scientists have sought to pharmacologically address human disease using a narrow focus–identify a key enzyme in a cellular process and block its active site with a complementary small molecule. More recently, monoclonal antibodies have proven successful at ameliorating disease states when the therapeutic target is in the extracellular space. Although both approaches have undoubtedly saved and improved lives, their utility has found limits–monoclonal antibodies are restricted to the extracellular space, and many intracellular proteins, such as protein–protein interaction targets (PPIs)–are refractory to traditional small molecule approaches due to the large and flat surfaces that mediate these interactions. Fortunately, novel approaches are emerging including targeted protein degradation (TPD), a strategy where selected proteins can be depleted via small molecules hijacking the endogenous cellular protein degradation machinery.

  • Targeting Lysosomal Degradation Pathways: New Strategies and Techniques for Drug Discovery

    March 25, 2021 Pei, Junping, Guan Wang, Lu Feng, Jifa Zhang, Tingting Jiang, Qiu Sun, and Liang Ouyang. A series of tools for targeted protein degradation are inspiring scientists to develop new drugs with advantages over traditional small-molecule drugs. Among these tools, proteolysis-targeting chimeras (PROTACs) are most representative of the technology based on proteasomes. However, the proteasome has little degradation effect on certain macromolecular proteins or aggregates, extracellular proteins, and organelles, which limits the application of PROTACs. Additionally, lysosomes play an important role in protein degradation. Therefore, lysosome-induced protein degradation drugs can directly regulate protein levels in vivo, achieve the goal of treating diseases, and provide new strategies for drug discovery. Lysosome-based degradation technology has the potential for clinical translation. In this review, strategies targeting lysosomal pathways and lysosome-based degradation techniques are summarized. In addition, lysosome-based degrading drugs are described, and the advantages and challenges are listed. Our efforts will certainly promote the design, discovery, and clinical application of drugs associated with this technology.

  • LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation

    March 25, 2021 Ahn, G., Banik, S.M., Miller, C.L. et al. Selective protein degradation platforms have afforded new development opportunities for therapeutics and tools for biological inquiry. The first lysosome-targeting chimeras (LYTACs) targeted extracellular and membrane proteins for degradation by bridging a target protein to the cation-independent mannose-6-phosphate receptor (CI-M6PR). Here, we developed LYTACs that engage the asialoglycoprotein receptor (ASGPR), a liver-specific lysosome-targeting receptor, to degrade extracellular proteins in a cell-type-specific manner. We conjugated binders to a triantenerrary N-acetylgalactosamine (tri-GalNAc) motif that engages ASGPR to drive the downregulation of proteins. Degradation of epidermal growth factor receptor (EGFR) by GalNAc-LYTAC attenuated EGFR signaling compared to inhibition with an antibody. Furthermore, we demonstrated that a LYTAC consisting of a 3.4-kDa peptide binder linked to a tri-GalNAc ligand degrades integrins and reduces cancer cell proliferation. Degradation with a single tri-GalNAc ligand prompted site-specific conjugation on antibody scaffolds, which improved the pharmacokinetic profile of GalNAc-LYTACs in vivo. GalNAc-LYTACs thus represent an avenue for cell-type-restricted protein degradation.

  • Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide

    March 2, 2021 Jan, Max, Adam S. Sperling, and Benjamin L. Ebert. Abstract For decades, anticancer targeted therapies have been designed to inhibit kinases or other enzyme classes and have profoundly benefited many patients. However, novel approaches are required to target transcription factors, scaffolding proteins and other proteins central to cancer biology that typically lack catalytic activity and have remained mostly recalcitrant to drug development. The selective degradation of target proteins is an attractive approach to expand the druggable proteome, and the selective oestrogen receptor degrader fulvestrant served as an early example of this concept. Following a long and tragic history in the clinic, the immunomodulatory imide drug (IMiD) thalidomide was discovered to exert its therapeutic activity via a novel and unexpected mechanism of action: targeting proteins to an E3 ubiquitin ligase for subsequent proteasomal degradation. This discovery has paralleled and directly catalysed myriad breakthroughs in drug development, leading to the rapid maturation of generalizable chemical platforms for the targeted degradation of previously undruggable proteins. Decades of clinical experience have established front-line roles for thalidomide analogues, including lenalidomide and pomalidomide, in the treatment of haematological malignancies. With a new generation of ‘degrader’ drugs currently in development, this experience provides crucial insights into class-wide features of degraders, including a unique pharmacology, mechanisms of resistance and emerging therapeutic opportunities. Herein, we review these past experiences and discuss their application in the clinical development of novel degrader therapies.

  • Reimagining Druggability Using Chemoproteomic Platforms

    March 18, 2021 Spradlin, Jessica N., Erika Zhang, and Daniel K. Nomura. Abstract Conspectus One of the biggest bottlenecks in modern drug discovery efforts is in tackling the undruggable proteome. Currently, over 85% of the proteome is still considered undruggable because most proteins lack well-defined binding pockets that can be functionally targeted with small molecules. Tackling the undruggable proteome necessitates innovative approaches for ligand discovery against undruggable proteins as well as the development of new therapeutic modalities to functionally manipulate proteins of interest. Chemoproteomic platforms, in particular activity-based protein profiling (ABPP), have arisen to tackle the undruggable proteome by using reactivity-based chemical probes and advanced quantitative mass spectrometry-based proteomic approaches to enable the discovery of “ligandable hotspots” or proteome-wide sites that can be targeted with small-molecule ligands. These sites can subsequently be pharmacologically targeted with covalent ligands to rapidly discover functional or nonfunctional binders against therapeutic proteins of interest. Chemoproteomic approaches have also revealed unique insights into ligandability such as the discovery of unique allosteric sites or intrinsically disordered regions of proteins that can be pharmacologically and selectively targeted for biological modulation and therapeutic benefit. Chemoproteomic platforms have also expanded the scope of emerging therapeutic modalities for targeted protein degradation and proteolysis-targeting chimeras (PROTACs) through the discovery of several new covalent E3 ligase recruiters. Looking into the future, chemoproteomic approaches will unquestionably have a major impact in further expansion of existing efforts toward proteome-wide ligandability mapping, targeted ligand discovery efforts against high-value undruggable therapeutic targets, further expansion of the scope of targeted protein degradation platforms, the discovery of new molecular glue scaffolds that enable unique modulation of protein function, and perhaps most excitingly the development of next-generation small-molecule induced-proximity-based therapeutic modalities that go beyond degradation. Exciting days lie ahead in this field as chemical biology becomes an increasingly major driver in drug discovery, and chemoproteomic approaches are sure to be a mainstay in developing next-generation therapeutics.

TPD Industry Events

  • Webinar: Degraders on The Rise - Targeted Protein Degradation in Drug Discovery

    May 26, 2021 03:00 PM in London The concept of Targeted Protein Degradation (TPD) covers all techniques that exploit the natural mechanisms of cellular degradation to target a disease-causing protein for destruction. The power of TPD, at least in principle, is that it allows the pursuit of what have previously been thought of as “undruggable” targets. But what are the different modalities of TPD, and, importantly, what should be considered when evaluating it as an approach?

  • Kisaco Research: North American Protein Degradation Congress 2021

    16-24 FEBRUARY, 2021 Once again bringing together leaders from pharma, biotech and academia as well as innovative service providers, the North American Protein Degradation Congress is back to give you the full picture from molecular biology right the way up to the latest in medicinal chemistry and clinical data. Learn to create clinically applicable degraders to the entire proteome at the digital North American Protein Degradation Congress 2021.

  • Dana-Farber Targeted Protein Degradation - The Webinar Series

    Bi-weekly Seminars exploring different mechanisms of small molecule mediated protein degradation for the development of chemical probes and/or drugs. The Webinar Series will take place bi-weekly on: Thursdays 12 pm noon (Eastern Standard Time) 9 am (Pacific Standard Time) 5 pm (British Summer Time) 6 pm (Central European Summer Time) You can join webinar by Zoom. https://dfci.zoom.us/webinar/register/WN_m7JJaw52T8yZYt8-ykL6UQ ​

  • Undruggable Leaders Forum

    SEPTEMBER 2021 | EST The Undruggable Leaders Virtual Forum, the pan-undruggable meeting serving senior decision-makers from pharma and biotech who are striving to discover and advance undruggable targets.

  • European Protein Degradation Congress 2021 | Kisaco Research

    SEPTEMBER 22-23, 2021 BASEL, SWITZERLAND Leading industry players from biotechs and big pharma will come together to exchange thoughts on how to best overcome obstacles to achieving reliable in vitro and in vivo data. Academic experts will be present their latest research to help build a deeper understanding of the mechanisms involved in the Ubiquitin pathway, providing a clearer picture on what makes a good, or not good, target for degradation.

  • Drug Discovery Chemistry Virtual: Ubiquitin-Induced Targeted Protein Degradation

    MAY 18-19, 2021 | ALL TIMES EASTERN DAYLIGHT (UTC-04:00) This conference brings together experts who can discuss the potential, as well as the challenges underlying targeted protein degradation as a new approach for therapeutic intervention.

  • Virtual Keystone Symposia: Targeted Protein Degradation: From Small Molecules to Complex Organelles

    June 7-8, 2021 | 10:00AM EDT | 2:00PM UTC | 4:00PM CEST* This conference will bring together researchers from these different fields, who do not typically interact, to build a holistic and integrated vision of protein degradation. Such an integrative conference highlighting the connections between the different branches of protein degradation research does not yet exist, so this Keystone Symposia conference will be the first of its kind to reshape how these fields interact and collaborate to yield transformative insights into both basic science and disease processes.

  • Targeted Protein Degradation Summit

    October 2021 The 4th Targeted Protein Degradation Summit returns in October 2021 to once again explore the latest approaches, perspectives, and data-drive case studies that will continue to advance PROTACs, molecular glues, and other degrader modalities towards clinical success.

  • Discovery on Target

    September 27-30, 2021 Discovery on Target (DOT) is the industry’s preeminent event on novel drug targets and technologies for drug discovery professionals. DOT highlights advances in current and emerging “hot” targets and technologies, as well as target validation strategies for the discovery and development of novel therapeutic agents, ranging from biologics to small molecules.

Video Animations

Video exemplifications are incredibly helpful. If you have good examples to share, please forward the link to be included in the TPD Digest.

  • THE PROTEASOME, UBIQUITINATION, AND PROTEIN DESTRUCTION

    Sources: The best article:

  • The Proteasome: The Cell's Trash Processor in Action

    #NIGMS #NIH This animation shows how the proteasome breaks down damaged or unwanted proteins into bits that the cell can reuse to make new proteins. Learn more about NIGMS and the research we fund: https://www.nigms.nih.gov/ Credit: Andreas Martin, University of California, Berkeley.

  • What is ubiquitin?

    Ubiquitin is a small protein that is used in cell signalling: it can get attached to all kinds of proteins inside a cell in order to change their behaviour, location, or protein-protein interactions. In this video, we go into a bit more detail around the different kinds of ubiquitynation, and what enzymes are required to attach ubiquitin to a target protein. References: - Yau & Rape, Nature Cell Biology 2016 - Buetow & Huang, Nature Reviews Molecular Cell BIology 2016

  • What is the proteasome?

    Cells are constantly building proteins to perform all kinds of different tasks inside a cell. But that also means that it can get quite crowded inside the cell, so it needs to get rid of proteins that are no longer needed. In a previous video, we've shown you how ubiquitin tags are attached to these unwanted proteins, flagging them for destruction. In this video, we're going into a bit more detail about how that destruction actually works, by looking at the cell's big protein shredder: the proteasome. Our video about ubiquitin: https://youtu.be/e29F7R3K_5A References: - Huang et al. Nature Structural & Molecular Biology (2016) - Koehler et al. Molecular Cell (2001) - Beck et al. PNAS (2012) - Unverdorben et al. PNAS (2014) - Aufderheide et al. PNAS (2015) - Schweitzer et al. PNAS (2016) - Wehmer et al. PNAS (2017)

  • Proteasome Animation 3D Molecular Biology

    DEMO VIDEO | This video depicts the proteasome degradation pathway. Ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2, and ubiquitin ligase (E3) are shown. We produce 3D, accurate, pedagogical cell and molecular biology animations for post-secondary education. For more information, please visit: www.smart-biology.com

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