Previous Speakers (2021 part 2)

Some seminars were recorded and accessible for a limited time on our youtube channel.

September 2nd, 2021 

30 years of Molecular Glues: Controlling cell circuitry in biology and medicine

 

Host: Alyssa Verano

 
 
 

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.

September 16th, 2021 

Host: Mikolaj Slabicki

Aline Renneville

"A thalidomide analog induces degradation of ZMYM2 fusion oncoproteins in hematologic malignancies".

Aline Renneville obtained her PharmD and PhD from the University of Lille, France. She worked as a molecular biologist in the hematology laboratory of Lille Hospital for several years. After completing her PhD, she joined Ben Ebert’s lab at Brigham and Womens’ Hospital as a post-doctoral fellow in 2014. While there, she focused on the induction of fetal hemoglobin using epigenetic modifiers as a therapeutic approach for sickle cell disease. From 2017 to 2019, she worked as a research scientist in the Cancer Program of the Broad Institute of MIT and Harvard, where she was involved in several projects related to targeted protein degradation through the CRBN-CRL4 E3 ligase complex using new thalidomide analogs. She moved back to France in 2020 and is now working at Gustave Roussy Institute in the Paris area, where she’s developing new projects with the goal of identifying novel therapeutic vulnerabilities in hematological malignancies.

Rob S Sellar

"Targeted protein degradation to treat AML: by accident and by design".​

 
Born Edinburgh.

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 

Ubiquitin-dependent degradation in development and disease.

Host: Mikolaj Slabicki

 
 
 

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.