Previous Speakers (2021 part 2)
Some seminars were recorded and accessible for a limited time on our youtube channel.
September 2nd, 2021
Host: Alyssa Verano
30 years of Molecular Glues: Controlling cell circuitry in biology and medicine
Dr. Schreiber’s research integrates chemical biology and human biology to advance both our understanding of chemistry and biology, and the discovery of novel therapeutics. He is known for his use of small molecules to explore biology and medicine, and for his role in the development of the field of chemical biology. With Jerry Crabtree in 1991, his lab mapped the first membrane to nucleus signaling pathway (calcium–calcineurin–NFAT). His lab co-discovered mTOR in 1994 (simultaneously with Sabatini) and helped illuminate the mTOR-dependent nutrient-response signaling network. His lab discovered histone deacetylase (HDAC) and, together with David Allis and Michael Grunstein in 1996, the role of chromatin marks in gene expression. His work demonstrated for the first time that drugs can result from: 1) the targeting of protein kinases (sirolimus/mTOR) and protein phosphatases (sandimmune/ calcineurin); 2) gene regulation by chromatin-modifying enzymes (vorinostat/HDAC), 3) chemical inducers of proximity (CIPs) that activate cellular processes by enforced proximity (GVH Disease), and 4) targeting of the proteasome (bortezomib/proteasome). His research illustrated that many small molecules are bifunctional and act by inducing proximity of signaling proteins, which he coined ‘molecular glues’. The discovery of molecular glues and development of chemical inducers of proximity led conceptually to the targeted degradation of proteins by small-molecule ‘PROTACs’. These efforts accelerated the development of many additional widely used drugs and more generally the field of chemical biology.
Schreiber’s development of diversity-oriented synthesis has led to the discovery of many promising agents, including a novel mechanism of action anti-malarial agent being developed in collaboration with the pharmaceutical company Eisai (Nature, 2017). His most recent discovery revealed a novel cell state responsible for the ability of cancers to resist a wide range of therapies, and a means to target the cancer therapy-resistant state (Nature, 2017). His research has been reported in over 650 publications (H index = 147; Schreiber Publications) and recognized through numerous awards, most recently the Arthur C. Cope Award and the Wolf Prize in Chemistry.
Four new anti-cancer drugs that target proteins discovered in the Schreiber laboratory have been approved by the U.S. FDA: temsirolimus (Wyeth) and everolimus (Novartis), which target mTOR (discovered using rapamycin in 1994), for renal cancer, and vorinostat (Merck) and romidepsin (Celgene), which target HDACs (HDAC1 discovered using trapoxin in 1996), for cutaneous T-cell lymphoma; in addition, topical HDAC inhibitor remetinostat (Medivir, PII clinical trials for CTCL), was conceived and synthesized in the Schreiber lab. A small-molecule molecular-glue drug (AP1903) reversed the effects of graft-versus-host disease in acute leukemia patients receiving hematopoietic stem cells engineered to express caspase-9 fused to a drug-responsive, FKBP12-based dimerization domain (NEJM, 2011). Proteins first shown by Schreiber to be targeted by a small molecule have been validated therapeutically by the FDA-approval process: tacrolimus (calcineurin/immunosuppression/1994; Schreiber’s study of FK506) and bortezomib (proteasome/multiple myeloma/2003; Schreiber’s study of lactacystin).
Schreiber extended chemical biology principles to medicine by participating in the founding of ten biotech companies, beginning with Vertex Pharmaceuticals, whose efforts have made cystic fibrosis a manageable disease. These companies have developed many novel therapeutic agents that are being tested in human clinical trials or used as FDA-approved drugs including: Vertex Pharmaceuticals (founded 1989: fosamprenavir/Lexiva; telaprevir/Incivek; ivacaftor/Kalydeco), ARIAD Pharmaceuticals (founded 1991: ponatinib/Iclusig; brigatinib/Alunbrig), ARIAD Gene Therapeutics (founded 1994: ridaforolimus; AP1903), and Infinity Pharmaceuticals (founded 2001: retaspimycin; duvelisib). Earlier stage chemical biology-based companies formed by Schreiber include: Forma Therapeutics, H3 Biomedicines, Jnana Therapeutics, Kisbee Therapeutics, Kojin Therapeutics and oNeir Therapeutics. In 2020, Schreiber co-founded Scientists to Stop COVID-19, a nonpartisan science-based group who advise policy makers in U.S. executive, congressional and state governments, as well as leaders in the sports and entertainment industries.
Link to the recorded seminar:
September 16th, 2021
Host: Mikolaj Slabicki
Aline Renneville
Gustave Roussy Institute
A thalidomide analog induces degradation of ZMYM2 fusion oncoproteins in hematologic malignancies
Rob S Sellar
UCL Cancer Institute
Targeted protein degradation to treat AML: by accident and by design
Clinical training Edinburgh, Oxford, London. PhD UCL
Post-doc Ebert Lab.
Now PI at UCL Cancer Institute. CRUK Advanced Clinician Scientist.
Leukaemia Biology and targeted Protein Degradation.
Consultant Haematologist - adult leukaemia service.
September 30th, 2021
Host: Mikolaj Slabicki
Michael Rape
University of California, Berkeley
Ubiquitin-dependent degradation in development and disease
Micha Rapé is a pioneer in uncovering molecular mechanisms of cell fate determination, using posttranslational modification with ubiquitin as his starting point. Micha’s work revealed essential ubiquitin signals, substrates and enzymes, as well as mechanisms of ubiquitylation that are essential for human development and disease. Most recently, Micha’s lab discovered the reductive stress response as a core regulator of mitochondrial activity and dimerization quality control, the first example of quality control of protein complex composition. His work led to the first prospective development of a molecular glues targeting E3 ligases, which greatly helped open up the ubiquitin system for drug discovery. To advance new ubiquitin-focused approaches in drug discovery, Micha co-founded Nurix Therapeutics with support from The Column Group.
Micha received his PhD at the Max-Planck Institute of Biochemistry, and he performed postdoctoral work in Marc Kirschner’s lab at Harvard Medical School. In late 2006, Micha joined the Department of Molecular and Cell Biology at the University of California at Berkeley, where he is currently the Dr. K. Peter Hirth Chair of Cancer Biology and a Professor of Cell and Developmental Biology. Micha is also an Investigator of the Howard Hughes Medical Institute. His work has been recognized with a Pew Scholar’s Award, the NIH Director’s New Innovator Award, the Vilcek Prize for Creative Promise honoring the best immigrant into biomedical sciences, and the National Blavatnik Award in Life Sciences.
Link to the recorded seminar:
October 14th, 2021
Host: Mikolaj Slabicki
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Targeting epigenetic proteins for novel cancer therapy development
Dr. Jun Qi is an Assistant Professor in Medicine at Department of Cancer Biology in Dana-Farber Cancer Institute, and Department of Medicine in Harvard Medical School. Dr. Qi received his BS from Fudan University in China, and obtained his Ph.D. in Chemistry from University of Michigan in 2006. He then completed his postdoctoral training at MIT in 2009. Dr. Qi joined Bradner laboratory at Dana-Farber Cancer Institute to lead the chemistry effort as well as polished his chemical biology and biology knowledge in 2009. He started his independent research group in July, 2017, and continue his research on developing chemistry, medicinal chemistry and chemical biology platforms to study a variety of biological targets and establish the understanding of their roles in cancer, including epigenetic writer, reader and eraser proteins.
Link to the recorded seminar:
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October 28th, 2021
Host: Radoslaw Nowak
Benika Pinch
Novartis Institutes for BioMedical Research
A Strategy to Assess the Cellular Activity of E3 Ligase Components against Neo-Substrates Using Electrophilic Probes
Benika Pinch is a Principal Scientist at Novartis Institutes for BioMedical Research, where her research is focused on applying chemical biology to exploratory drug discovery projects. She received her B.A. in Biochemistry and M.S. in Chemistry from the University of Pennsylvania in 2014, and her Ph.D. in Chemical Biology from Harvard University in 2019. At Harvard, she worked in Dr. Nathanael Gray's laboratory characterizing bifunctional kinase degraders and developing covalent chemical probes.
Seth Carbonneau
Novartis Institutes for BioMedical Research
An IMiD-inducible degron to reversibly regulate CART therapy
Seth Carbonneau is a graduate of College of the Atlantic in Bar Harbor, ME and has worked with Dr. James Coffman at the Mount Dessert Island Biological Laboratory, with Dr. Thomas Look at the Dana Farber Cancer Institute, and at Novartis Institutes for BioMedical Research in Chemical Biology and Therapeutics. His research has touched the fields of developmental biology, genetics, and chemical biology, with a focus in assay technologies, targeted protein degradation, and exploratory drug discovery.
Link to the recorded seminar:
Rewiring the Extracellular Interactome for Targeted Protein Degradation
Steven Banik is an Assistant Professor the Department of Chemistry and a ChEM-H Institute Scholar at Stanford University. He received his B.S. from the University of Wisconsin, and his Ph.D. in Chemistry from Harvard University working with Dr. Eric Jacobsen. Steven performed postdoctoral studies with Dr. Carolyn Bertozzi at Stanford University where he developed Lysosome-Targeting Chimeras (LYTACs). Steven began his independent career in January of 2021. At Stanford, Steven’s group combines chemical biology, molecular biology, genomics, proteomics, and protein engineering for translational tool development and the study of biological mechanisms.
Link to the recorded seminar:
November 18th, 2021
Host: Radek Nowak
Katherine Donovan
Dana-Farber Cancer Institute / Harvard Medical School
Large-Scale Chemoproteomic Profiling Surveys the Degradable Proteome for Accelerated Degrader Development
Katherine Donovan is a Senior Scientist in the Fischer Lab at Dana-Farber Cancer Institute and Harvard Medical School where she works on the development of molecular-glues and PROTAC molecules for targeted protein degradation. She completed her PhD training in protein biochemistry and structural biology at the University of Canterbury, New Zealand. After joining the Fischer Lab as a Postdoc she developed an interest in proteomics as a specialized technology for quantifying protein-level expression changes in response to various perturbations. Katherine set up and optimized and led a high throughput proteomics pipeline in the Fischer Lab as well as in the Center for Protein Degradation. She has used this proteomics technology to identify the degradation targets of many molecules including the identification of SALL4 as the protein likely underlying the teratogenicity of thalidomide, she also mapped the degradable kinome and HDACome. Katherine continues to work on several projects related to ligase biology and protein degradation and also leads the degradation proteomics operation in the Fischer Lab.
Link to the recorded seminar:
Wubing Zhang is a Ph.D. student in Shirley Liu lab. He's research focuses on identifying novel therapeutic targets in cancer by machine learning modeling and integrative mining of high-throughput data.
December 2nd, 2021
Host: Katherine Donovan
Wubing Zhang
Dana-Farber Cancer Institute
Machine learning modeling of protein-intrinsic features predicts tractable targets of protein degraders
Markus Queisser
GSK
High Throughput Approaches in Targeted Protein Degradation and PROTAC Synthesis
Markus got interested in protein degradation during his Master’s in Biochemistry at Free University Berlin, where he worked on understanding proteasome function. He further gained broad knowledge in respiratory diseases, inflammation and oncology while pursuing a Ph.D. in Biomedical Sciences at an international graduate programme at UGLC in Germany and Albert-Einstein College of Medicine. Markus then moved on to postdoctoral training at Northwestern University, where in collaboration with Noble Laureate Aaron Ciechanover, he characterised the regulation of ubiquitin ligase HOIL as a key mechanism of tumor adaptation to hypoxia. Prior to joining GSK, he specialized in ubiquitin-ligase recruitment at the Ludwig Institute for Cancer Research. Currently, Markus is a GSK Fellow and Scientific Director in the Protein Degradation Group at GSK, leading the technology team and multiple collaborations with biotechs and academia.
Link to the recorded seminar:
December 16th, 2021
Host: Katherine Donovan
5 Selected Trainee Short Talks
Chao Sun - Max Planck Institute for Brain Research
Subcellular Stoichiometry of Neuronal Proteasome Assembly
Dr. Chao Sun is an EMBO & HFSP postdoctoral fellow in Prof. Erin M. Schuman's lab at Max Planck Institute for Brain Research, Germany. His current research uses quantitative, multiplexed super-resolution microscopy to investigate the molecular resource supply for the vast population of synapses associated with a single neuron. He obtained his PhD with Prof. William R. Dichtel at Cornell University, US (now at Northwestern University, US), where he designed and manipulated molecular interactions to interface two-dimensional materials and molecular analogues for creating smart nano- materials and devices. His future research continues to focus on understanding and creating molecular systems that can 'think'.
Nan Bai - Amgen
Modeling CRL4A ligase complex to predict target protein ubiquitination induced by CRBN-recruiting PROTACs
I completed my PhD in Dr. John Karanicolas’ lab at Fox Chase Cancer Center (2012-2019), and my dissertation is about small molecule drug design. In my PhD lab, we use computational tools to study drug/target interactions and to further rationally design more effective drugs. During my PhD journey, one of my projects was focused on modeling PROTAC-mediated ternary complex formation. I am really attracted by this PROTAC concept and would like to explore more about this class of promising therapeutics. In 2020, I was very fortunate to join the Pharmacokinetics and Drug Metabolism (PKDM) group of Amgen as a postdoc and started to work on more PROTAC related projects. In my current work, we propose a structure-based computational approach to predict CRBN-based PROTAC induced target protein ubiquitination by integrating ternary complex and CRL4A ligase complex structural information.
Daniel Zaidman - University of Cambridge
PRosettaC: Rosetta Based Modeling of PROTAC Mediated Ternary Complexes
Daniel Zaidman started his studies in Tel-Aviv University, Israel, and finished a dual B.Sc. in mathematics and computer science. He then proceeded to do his master degree in bioinformatics in the lab of Prof. Haim Wolfson in Tel-Aviv University. In his masters he worked on designing inhibitory peptides for protein-protein interactions. He did his PhD in the lab of Dr. Nir London in the Weizmann Institute, where he worked on computational protocols for two uprising domains in drug discovery, namely, covalent inhibitors (such as Ibrutinib, Afatinib, etc.), and protein degraders (PROTACs). For both of these fields, he developed elegant protocols, combining novel ideas, end-to-end implementation and interactive web-servers to use the algorithms he developed. Currently he is pursuing his postdoc in the University of Cambridge, in the lab of Dr. Gonçalo Bernardes. Outside the university, his interests include foreign languages and Buddhist meditation.
Xiuxiu Lu - NCI/NIH
Structure-guided hRpn13-targeting bifunctional molecules as chemical probes of hRpn13 dysfunction
Dr. Xiuxiu Lu received her Ph. D. from the Shanghai Institute of Organic Chemistry, CAS for her structural studies that yielded a new model of DNA cytidine deaminase APOBEC3G with HIV single-stranded DNA in an active orientation. In 2014, Dr. Lu joined NCI/NIH as a postdoctoral fellow and was promoted to a research fellow in 2019. Dr. Lu solved the structure of ubiquitin receptor hRpn13 with its docking site at the proteasome by NMR and applied biochemical assays to provide novel insights into the potential of hRpn13 and its associated deubiquitinating enzyme Uch37 as anticancer targets. Dr. Lu has identified a chemical scaffold to target hRpn13 and found the lead compound XL5 to reduce cellular viability in cancer cell lines. By solving the structure of hRpn13 with XL5, Dr. Lu expanded the small molecule to include Proteolysis Targeting Chimeras (PROTAC) technology, yielding bifunctional molecules with greater efficacy in cellular assays.
Agatheeswaran Subramaniam - Lund University
UM171 promotes ex vivo expansion of hematopoietic stem cells by targeting the epigenetic modulator CoREST for degradation
Agatheeswaran Subramaniam is an associate researcher at Lund University and currently trying to establish his own research group. Agathees did his master’s in biotechnology (Bharathidasan university) PhD in leukemia biology (Utkal University) from India. Agathees is interested in developing targeted therapies for selectively eliminating cancer propagating cells. During his postdoctoral research, he unraveled the targeted protein degradation mechanism of a small molecule UM171 and actively developing a research program in this field.
Link to the recorded seminar: https://youtu.be/VDUg9CLMtqE