Targeted Protein Degradation (TPD) is a revolutionary technology that reprograms the protein homeostasis system to destroy specific target proteins. In recent years, the rapid innovation and expansion of TPD technology platforms and methods have greatly expanded the scope of drug discovery, demonstrating huge therapeutic potential in preclinical studies of various diseases and attracting widespread attention from the global academic community, the pharmaceutical industry, and investors. To promote cooperation, innovation, and knowledge exchange among scientists from different disciplines in academia and industry, the Shenzhen Medical Academy of Research and Translation (SMART) and the Shenzhen Bay Laboratory (SZBL) jointly hosted the SMART Targeted Protein Degradation Symposium from November 12th to 14th, 2024, at the Shenzhen Guangming Cloud Valley International Convention Center.
The members of the organizing committee of this symposium included Nieng Yan, the founding president of SMART, the director of SZBL, and a professor at Tsinghua University; Nathanael Gray, a professor at Stanford University and the founder of Matchpoint Therapeutics and C4 Therapeutics; Alessio Ciulli, a professor at the University of Dundee, the director of the Centre for Targeted Protein Degradation (CeTPD), and the founder of Amphista Therapeutics; Peng Chen, a professor at Peking University and the convener of the Institute of Chemical Biology at SZBL; and Shixiang Yan, a partner of Bencao Capital. The conference invited dozens of scientists with diverse backgrounds from all over the world as keynote speakers and attracted more than 300 scholars from both domestic and foreign countries. Focusing on the three themes of "Discovery Chemistry and Design", "Molecular Mechanisms and Biology", and "Therapeutic Development", in-depth discussions were held on the successes, emerging trends, and future challenges in the field of TPD.
At the beginning of the conference, Professor Peng Chen, the co-chair of the conference, delivered the opening speech, welcoming everyone to Shenzhen to participate in this conference and hoping that the conference could help the participants exchange the latest research progress, jointly explore the frontiers of the discipline, and promote cross-disciplinary academic dialogue and cooperation.
The "Proteolysis-Targeting Chimeras (PROTAC)" session kicked off the conference. The PROTAC technology is an innovative targeted protein degradation strategy that simultaneously recruits the target protein and the E3 ubiquitin ligase through a small molecule chimera, inducing the polyubiquitination of the target protein and its subsequent degradation by the proteasome. Professor Giulia Caron from the University of Turin introduced the "chameleonicity" of PROTAC molecules. PROTAC molecules rationally optimized and designed by utilizing this property can simultaneously achieve high water solubility and high permeability, improving oral bioavailability. Professor Vesna Vetma from the University of Dundee introduced the structure-guided design of pan-KRAS degrading molecules targeting the key tumor target KRAS and their progress in tumor treatment. Professor Shaomeng Wang from the University of Michigan introduced the development of degrading molecules targeting the difficult-to-drug target STAT3 and the mechanism research on how STAT3 degradation inhibits tumor growth. Professor Maria-Laura Bolognesi from the University of Bologna introduced the exploration of targeting and degrading endogenous proteins of parasites, hoping to achieve the treatment of parasitic infections through this approach. Professor Alessio Ciulli detailed the latest progress in the structural mechanism study of PROTAC molecules inducing substrate ubiquitination, revealing the importance of the position of lysine on the surface of the target protein in the degradation complex for its ubiquitination efficiency and degradation induction. Later, Professor Alessio Ciulli also introduced the design and development of degrading molecules that simultaneously bind to multiple E3 ligases, further improving the degradation efficiency of the target protein. Professor Jian Jin from the Icahn School of Medicine at Mount Sinai introduced the development of new PROTAC technologies targeting "undruggable" targets that are difficult to target with small molecules, including Bridged PROTAC and TF-PROTAC. These technologies can induce the polyubiquitination and degradation of target proteins by targeting other members in the target protein complex or through nucleic acid sequences specifically recognized by transcription factors.
Entering the second session of the symposium, many experts and scholars gave wonderful reports around "Molecular Glues and the Proximity Effect". Dr. Tasuku Ishida from Elix introduced intramolecular bivalent molecular glues. Different from traditional PROTAC molecules, bivalent molecular glues can simultaneously bind and connect two adjacent domains of the target protein to achieve targeted protein degradation. Professor Nathanael Gray introduced covalent molecular glues designed by combining proximity chemistry and molecular glue design, achieving stronger degradation effects while maintaining selectivity. Professor Nathanael Gray also introduced the use of proximity chemistry-induced (CIP) to reverse the function of transcription factors in cells. By inducing the connection between BRD4 and BCL6, it initiates the transcription of pro-apoptotic genes downstream of BCL6. Through transcriptional activation rather than the traditional inhibitory effect, it realizes the killing of tumor cells. Dr. Andrea Testa from TRIMTECH Therapeutics introduced the use of the TRIM21 protein to achieve specific degradation of target proteins in the form of aggregates and the development of new therapies targeting tau protein aggregates using this technology. Encouragingly, after treating aged mice carrying tau protein aggregates, the progression of neurodegenerative symptoms in the mice was slowed down, and their motor functions were significantly improved. Immediately after that, Professor Ting Han from the Beijing Institute of Life Sciences introduced the discovery of molecular glues binding to the TRIM21 protein and the design of selective degrading molecules for the poly-cGAS protein based on this molecular glue. Professor Yong Cang from Shanghai University of Science and Technology introduced the GlueXplorer platform, which discovers, validates, and optimizes molecular glue degraders for specific disease targets through screening methods such as phenotyping, proteomics, and proximity chemistry-induced screening.
On the second day of the conference, the focus was first on the session of "Discovery and Development of Protein-Targeted Degradation Drugs". Dr. Manfred Koegl from Boehringer Ingelheim Vienna Branch introduced the exploration of developing targeted degradation molecules for short-half-life proteins and the challenges encountered in the process. Dr. Joachim Rudolph from Genentech introduced the development of monovalent degrading molecules targeting the SWI/SNF chromatin remodeling complex members SMARCA2/A4 proteins. Professor Guangrong Zheng from the University of Florida introduced the development and clinical research progress of selective degrading molecules for the apoptosis-regulating proteins Bcl-xL and Bcl-2. Dr. Michael Berlin from Arvinas introduced the company's TPD drug R&D pipeline and shared the clinical research progress of the LRRK2 protein degradation drug ARV-102. CMO Lin Wei from Revolution Medicines shared the development of molecular glue drugs targeting activated RAS. Their designed drug RMC-6236, by jointly binding with the CYPA protein to the GTP-bound conformation of the RAS protein, achieves the targeted degradation of activated RAS and significantly prolongs the survival period of pancreatic cancer (PDAC) patients in Phase 1b clinical data. Dr. Kate Jackson and Dr. Mathew Sowa from C4 Therapeutics respectively introduced the development of targeted BRD9 degradation drugs and targeted BRAF V600 mutant degradation drugs and their research progress in tumor treatment. Dr. Gwenn Hansen, the Chief Scientific Officer of Nurix Therapeutics, introduced the development and clinical research progress of pan-BRAF degradation drugs. Compared with traditional tyrosine kinase inhibitor drugs, degradation drugs have shown stronger tumor inhibitory effects and a wider range of tumor inhibitory types.
Next, the symposium entered the session of "Membrane Protein-Targeted Degradation". Professor Peng Chen introduced the membrane protein degradation technology GlueTAC developed based on covalent nanobodies and cell-penetrating peptides that induce target endocytosis. Based on GlueTAC and by introducing masking peptides, the degradation technology ProMPD, which is activated in situ in the tumor microenvironment, was further developed, reducing the off-target binding side effects of degradation molecules outside the tumor. Professor Peng Wu from the Scripps Research Institute shared the tools for targeting tumor cell desialylation and the research work on changing the tumor microenvironment by targeting and degrading Siglec-7 and -9 proteins. The degradation of Siglec-7 and -9 proteins can significantly enhance the anti-tumor immune activity of T cells, prolong T cell memory, and simultaneously enhance the antigen-presenting ability of macrophages, thereby controlling tumor growth. Professor Weiping Tang from the University of Wisconsin-Madison introduced the method of antibody-conjugated tri-GalNAc-mediated membrane protein-targeted degradation and the platform Rapid-TAC for rapidly synthesizing PROTAC molecule libraries using modular ligands. Professor Boxun Lu from Fudan University shared the protein-targeted degradation technology ERADEC based on a brand-new degradation mechanism.
The session on the final day of the conference was "Structural Biology, Omics, and New Configurations of Protein-Targeted Degradation". Professor Behnam Nabet from the Fred Hutchinson Cancer Center introduced the protein degradation tag dTAG technology. By fusing the FKBP12 F36V tag onto the target protein, a single degradation molecule that only recognizes the tag can play a degradation role on different target proteins. Professor Behnam Nabet further introduced the use of this system to discover drug targets and the research work on establishing tumor models to study the physiological functions of the targets. Professor Ning Zheng from the University of Washington introduced the structural mechanism by which the molecular glue UM171, with the assistance of inositol hexakisphosphate, achieves the degradation of the CoREST-HDAC1 complex, and conducted an in-depth analysis of the connection between the complex structure and mutations of target proteins in tumors. Researcher Katherine Donovan from the Dana-Farber Cancer Institute introduced the research work on exploring degradation molecule substrates based on high-throughput proteomics and AI structure prediction. Professor Yu Rao from Tsinghua University introduced controlling phase separation by targeting and degrading the BRD4 protein and the Degradation-Based Proteomics Profiling (DBPP) process. Professor Tinghu Zhang from Stanford University introduced the development of covalent molecular glue drugs. Dr. Yue Xiong, the Chief Scientific Officer of Cullgen, shared the development of TRK protein degradation molecule-antibody conjugates and their exploration in tumor and pain treatment. Professor Weihong Tan from the Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, shared the related work of Aptomics, introducing the research on the use of nucleic acid aptamers for cell screening, protein-targeted degradation, and cell type analysis. Dr. Hannah Maple from Bio-Techne introduced the covalent BromoTag protein tag technology. Through the improvement of the BD2 domain of BRD4 and its ligand molecules, the covalent BromoTag can achieve covalent labeling and induced degradation of the target protein.
During the question and answer session at the venue, the atmosphere was lively and active, and the participants showed extremely high enthusiasm for participation. The poster display session during the breaks between reports each day also attracted a lot of discussions, with many viewers having in-depth exchanges with the authors of the posters and sharing their ideas and inspirations with each other. The conference also selected the Best Poster Award, and the awardees took photos with the guests.
At the end of the conference, Professor Alessio Ciulli and Professor Nieng Yan, the co-chairs of the conference, delivered the closing speeches, thanking all the guest speakers for their sharing and the participants for their support, expressing their joy in the in-depth exchanges and discussions at the conference, and their expectation for holding the conference again in the future. The SMART Targeted Protein Degradation Symposium came to a successful conclusion. This conference conducted in-depth exchanges on the technological development, mechanism research, drug discovery, structural optimization, and clinical application of targeted protein degradation. It is worth mentioning that this SMART symposium simultaneously invited a large number of scientists from academia and industry, and many scientists from universities or research institutes were also involved in enterprise R&D work or served as scientific advisors. Thanks to this, the conference not only strengthened academic communication among global scientists but also promoted the exchange and integration of academia and industry. It is believed that inspired by this conference, targeted protein degradation technology and drug development will achieve more brilliant breakthroughs and developments.
Source: SMART International Exchange Center
Executive Editor: Winston
Editor: Paula Bao
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