У нас вы можете посмотреть бесплатно Nathanael Gray - Rewiring Transcription Using Chemically Induced Proximity или скачать в максимальном доступном качестве, видео которое было загружено на ютуб. Для загрузки выберите вариант из формы ниже:
Если кнопки скачивания не
загрузились
НАЖМИТЕ ЗДЕСЬ или обновите страницу
Если возникают проблемы со скачиванием видео, пожалуйста напишите в поддержку по адресу внизу
страницы.
Спасибо за использование сервиса ClipSaver.ru
Nathanael Gray is the Krishnan-Shah Family Professor of Chemical and Systems Biology at Stanford, Co-Director of Cancer Drug Discovery, Co-Leader of the Cancer Therapeutics Research Program, Member of Chem-H, and Program Leader for Small Molecule Drug Discovery for the Innovative Medicines Accelerator (IMA). His research uses the tools of synthetic chemistry, protein biochemistry, and cancer biology to discover and validate new strategies for addressing anti-cancer targets. Dr. Gray’s research has had broad impact in the areas of kinase inhibitor and degrader design and in circumventing drug resistance. Dr. Gray’s generalized strategy for structure-based design of inhibitors that stabilize the inactive kinase conformations (type II) has been widely adopted by the research community and has had a significant impact on the development of numerous inhibitors of tyrosine kinases that are currently undergoing clinical development. Abstract: “Rewiring Transcription Using Chemically Induced Proximity” Molecular glues are small molecules that exert their pharmacological effects by inducing new protein-protein interactions. Originally identified as the mechanism of natural product macrocycles such as rapamycin and FK506, the discovery of new molecular glues has experienced a resurgence of interest. A key driver of this interest has been the development of both monovalent and bivalent molecular glues for E3 ligases that can induce ubiquitination and proteosome-mediated destruction of target proteins. Here we report the development of a new class of molecular glues targeting transcription factors which are DNA-binding proteins that regulate gene expression in mammalian cells. We focused on Bcl-6 which is a transcription factor that is critical to B-cell development but that becomes an oncogene in B-cell lymphomas such as Diffuse Large B-Cell Lymphoma (DLBCL) and Chronic Lymphocytic Leukemia (CLL). We developed a series of bivalent small molecules that we call transcription factor induced chemical inducers of proximity (TCIPs) that induce neo-protein-protein interactions between Bcl6 and either the transcriptional co-activator protein Brd4 (TCIP1) or the RNA-pol2 kinase Cdk9 (TCIP2). We demonstrate that these molecules function as molecular glues that can convert Bcl6 from a transcriptional repressor to a potent activator of the apoptotic cell death program. We demonstrate that the compounds rapidly modulate the Bcl6 gene expression program and induce apoptotic cell-death in Bcl6-dependent cellular models at picomolar concentrations. The lead compounds exhibit efficacy in PDX and germinal center Bcell murine models at well-tolerated doses. This works provides proof-of-concept that transcription factors can be reprogrammed by molecular glues which opens a host of therapeutic opportunities in oncology and many other diseases. Learn more about The Welch Conference: https://welch1.org/conference/confere...