PAST SeminarS

IDP Conversations

02 JUNE 2021 | 11AM (EDT) / 5PM (CEST)

Machine learning and statistical inference techniques to describe intrinsically disordered protein ensembles

We present our recent work in building ML/AI approaches to describe conformational transitions within intrinsically disordered protein ensembles (IDPs). IDPs challenge the traditional protein structure–function paradigm by adapting their conformations in response to specific binding partners leading them to mediate diverse, and often complex cellular functions such as biological signaling, self-organization and compartmentalization. Obtaining mechanistic insights into their function can therefore be challenging for traditional structural determination techniques. Often, scientists have to rely on piecemeal evidence drawn from diverse experimental techniques to characterize their functional mechanisms. Multi-scale simulations can help bridge critical knowledge gaps about IDP structure-function relationships — however, these techniques also face challenges in resolving emergent phenomena within IDP conformational ensembles. We posit that ML/AI techniques can effectively integrate information gleaned from multiple experimental techniques as well as from simulations in obtaining quantitative insights into complex/ emergent phenomena within these biological systems.  We highlight three different aspects of ML/AI approaches: (1) in building biophysically meaningful collective variables that describe conformational transitions in IDP ensembles; (2) using AI-driven approaches to sample rare conformational fluctuations in IDP conformational landscapes; and (3) integrating small angle scattering and nuclear magnetic resonance experiments to probe conformational states accessed and to refine force-field parameters based on their collective descriptions. Together, our approaches highlight how ML/AI could be an integrated aspect for probing IDP-mediated biological phenomena. 

Arvind Ramanathan is a computational biologist in the Data Science and Learning Division at Argonne National Laboratory and a senior scientist at the University of Chicago Consortium for Advanced Science and Engineering (CASE). His research interests are at the intersection of data science, high performance computing and biological/biomedical sciences. His research focuses on developing principled and scalable statistical inference techniques for analysis and development of adaptive multi-scale molecular simulations for studying complex biological phenomena (such as how intrinsically disordered proteins self assemble, or how small molecules modulate disordered protein ensembles). He obtained his Ph.D. in computational biology from Carnegie Mellon University, and was the team lead for integrative systems biology team within the Computational Science, Engineering and Division at Oak Ridge National Laboratory.  More information about his group and research interests can be found at here.

07 JULY 2021 | 11AM (EDT) / 5PM (CEST)

From a Design on a Napkin to a Clinical Trial: a 20-year quest to improve survival for Ewing sarcoma patients

In 2009, Dr. Toretsky and his team revealed the molecule called YK-4-279 that targets Ewing sarcoma with an article in Nature Medicine. A deeper investigation into the mechanism of YK-4-279 has led Dr. Toretsky into the world of phase separation and soft matter. An analog of YK-4-279 called TK216 is in human clinical trials and seems to be helping some patients. This is the story that will be told.

Dr. Jeffrey Toretsky received his MD in 1988 from the University of Minnesota. He completed his pediatric residency at the Medical College of Virginia in 1991, and his pediatric oncology fellowship at the National Cancer Institute Pediatric Branch in 1997. In 2002, Dr. Toretsky was recruited from the University of Maryland to Georgetown University; where he was promoted to full professor with tenure in 2011. He was inducted into the American Society of Clinical Investigation in 2007 and received the Burroughs-Wellcome Clinical Scientist Award in Translational Research in 2008. In 2018, Toretsky was inducted into the National Academy of Inventors.
Dr. Toretsky actively pursues research that will lead to new and more specific therapies for a very rare cancer, Ewing sarcoma. His work focuses on Ewing sarcoma, since the tumors contain a unique target that is not found in non-tumor cells. This unique target offers an opportunity to create new medicines that will more specifically eliminate tumor growth while sparing normal cells. In 2009, Dr. Toretsky and his team revealed the molecule called YK-4-279 that targets Ewing sarcoma with an article in Nature Medicine. YK-4-279 has the potential to be a potent new strategy in the fight against not only Ewing sarcoma, but also other cancers and diseases with similar characteristics. A deeper investigation into the mechanism of YK-4-279 has led Dr. Toretsky into the world of phase separation and soft matter. He is particularly interested in understanding how protein complexes he called ‘assemblages’ occur and how they function in RNA processing. Along with this, he cofounded Tokalas, Inc., now Oncternal, Inc., to advance YK-4-279 to a clinical trial that began in the spring of 2016. 
Dr. Toretsky is now Chief of the Division of Pediatric Adolescent and Young Adult Hematology/Oncology at Georgetown University. He continues to be the principal investigator of his NIH-funded laboratory group, leads the Molecular Oncology Program of the Lombardi Comprehensive Cancer Center, and co-leads a multidisciplinary sarcoma clinic at Children’s National Medical Center. He continues to be engaged in teaching at levels from high school through faculty mentoring. His wife, three children, dogs (Lucy and Greta), a passion for SCUBA diving and a clarinet support him in these endeavors.

01 SEPT 2021 | 11AM (EDT) / 5PM (CEST)

Drugging Important Cancer Targets Like KRAS

Numerous highly validated drug targets in oncology remain undrugged despite many of them being discovery 40 years ago. Boehringer Ingelheim is targeting many of these proteins in its drug discovery efforts – with KRAS being a target of particular focus. KRAS drives 1 in 7 of all human cancers and 90% of the KRAS driven cancers are caused by 9 different KRAS mutants. It took 39 years for the first drug approval against the first KRAS mutant KRASG12C after Channing Der’s discovery in 1982 that KRAS is an oncogene. But KRASG12C is but one of the 9 major cancer causing KRAS mutants and resistance, both intrinsic and acquired, appears to limit response rates and duration of response. This talk will provide an overview of the field and highlight the current and future challenges that need to be overcome. The talk will also highlight the multiple pan-KRAS and selective KRAS concepts that Boehringer-Ingelheim is pursuing to drug all forms of KRAS. The specific programs that will be presented include pan-KRAS inhibitors and pan-KRAS PROTACs (Proteolysis Targeting Chimeras), selective KRASG12C and KRASG12D inhibitors and SOS1 inhibitors. Historical screening efforts, particularly in the protein-protein interaction field, including successes and pitfalls will be also mentioned.

Darryl McConnell is currently Senior Vice President and Research Site Head at Boehringer-Ingelheim Regional Centre Vienna, Austria. His goal is to discover new chemical therapeutics for cancer’s Big 4 and beyond with the team at BI. Darryl’s interests lie in drugging protein-protein interactions, kinases and pushing the frontiers of PROTACs for cancer patients. Fragment screening, protein crystallography, protein NMR, drug resistance and natural product inspired medicinal chemistry are some of his areas of scientific interest.

Darryl commenced his career with Boehringer-Ingelheim in 2002 as a Research Laboratory Head and has been in his current role since 2015. Prior to this Darryl has worked for Intervet in Vienna from 2001, for Biota Holdings Ltd in Melbourne, Australia from 1999 in the area of respiratory viruses and Chiron Technologies in Melbourne from 1997. Darryl McConnell received his Bachelor of Science with First Class Honours in 1991 with Professor John Elix at the Australian National University in Canberra. He performed his PhD at the University of New South Wales in Sydney with Professor David Black for which he was awarded the Cornforth Medal for the best chemistry PhD thesis in Australia for that year. Following this he performed a 2 year Postdoctoral study at the University of Sydney with Professor Leslie Field in organometallic chemistry.

06 OCTOBER 2021 | 11AM (EDT) / 5PM (CEST)

Development of drugs that directly target the intrinsically disordered region of N-terminal domain of androgen receptor

Androgen receptor is a transcription factor and validated therapeutic target for prostate cancer. All currently approved inhibitors of androgen receptor target its folded C-terminus ligand-binding domain. Resistance to these therapies is mediated by expression of constitutively active splice variants of androgen receptor that are truncated and lack a ligand-binding domain. Thus targeting the intrinsically disordered N-terminal domain of androgen receptor provides a novel therapeutic mechanism. Here we report our approach to the discovery and clinical development of small molecule inhibitors of this drug target previously considered to be “un-druggable”.

Dr. Sadar is a Professor of Pathology and Laboratory Medicine at the University of British Columbia and Distinguished Scientist in the Department of Genome Sciences at BC Cancer. Dr. Sadar’s research has focused on identifying mechanisms of transactivating the androgen receptor which is a therapeutic target for prostate cancer and other diseases. Uniquely her research has focused on developing therapies to the intrinsically disordered N-terminal domain of the androgen receptor which acts as a hub for essential protein-protein interactions required for its transcriptional activity. She has identified the first small molecule inhibitors that directly bind to the N-terminal domain of androgen receptor that has yielded compounds that have been taken into clinical trials. Her first-in-class compounds were granted a new stem class from the USAN council “-aniten”. Related work includes developing imaging agents with small molecules that bind to unique regions of the N-terminal domain of androgen receptor. Her current areas of research interest are concentrated predominantly on indications for prostate cancer and breast cancer.

Dr. Sadar is a co-founder, and past Director and Officer of ESSA Pharma Inc. (EPIX, NASDAQ). She has served in leadership positions such as President of the Society of Basic Urologic Research and the Y2017 Chair of the USA Army’s Department of Defence’s Programmatic Panel for their Prostate Cancer Research Program. Dr. Sadar has served on over 50 grant panels including 5 years on the NIH study session for Drug Discovery & Molecular Pharmacology.