Histone Lysine Methyltransferases-Conformational Dynamics and Selective Inhibitor Design for Chromatin-Modifying Enzymes in Lymphomas and Melanomas
Abstract
I, Rafal Wiewiora, am a Graduate Student at the Tri-Institutional PhD Program in Chemical Biology at Weill Cornell Graduate School. I hold a Master of Chemistry degree from the University of Oxford. I have strong potential for a career in chemical biology of cancer. My goal is to become faculty at a world leading institution, working on structural biology and biophysics of cancer-implicated epigenetic proteins, and chemical probe and drug discovery for those targets, combining state-of-the-art computational design approaches and robotic laboratory. My mentor, Dr. John Chodera holds an appointment of Assistant Member in the Computational Biology Program at the Sloan Kettering Institute. His research focuses on the use of rigorous statistical mechanics, physical modeling, and statistical inference to develop quantitative, predictive computational models to enable the engineering of small molecules with desired properties. My co-mentor, Dr. Minkui Luo holds an appointment of Associate Member in the Chemical Biology Program at the Sloan Kettering Institute. The long-term goal of the Luo laboratory is to use chemical tools to define, perturb and manipulate the functions of protein methylation for cancer diagnosis and therapy. Epigenetic routes to cancer initiation and progression have now been appreciated and offer great potential for more targeted and effective therapeutics. Histone lysine methyltransferases (HKMTs) are one class of proteins broadly implicated in a variety of cancers, where dysregulation of the histone methylation can result in suppression of the transcription of tumor suppressor genes or increase in the transcription of oncogenes. While it has been appreciated that histone lysine methyltransferases are generally conformationally-flexible, and the impact of this flexibility on chemical probe and drug design for this protein class has been illustrated through a number of examples, our knowledge about the detailed conformational landscapes of HKMTs remains scarce. This can be compared to the beginnings of the kinase research, where the appreciation of the structural nuances has resulted in a much thorough understanding on the requirements of small molecules targeting those proteins and the problems associated with such a goal. In this project, we propose to use very long timescale (millisecond aggregate length) Molecular Dynamics simulations of two important epigenetic cancer targets: histone lysine methyltransferases EZH2 (lymphoma and melanoma targets) and SETB1 (melanoma target). Through activating mutations and overexpressions, these proteins have been associated with disease initiation and aggressiveness in those cancers, and proposed as therapeutic targets. Through the Molecular Dynamics simulations, we plan to learn about the distinct conformational states adopted by these proteins, and hence enumerate many more binding modes and binding pockets in these proteins, than has been appreciated from the available static X-ray structures. Furthermore, we will in silico design novel small molecule scaffolds to utilize the novel binding pockets, and validate these predictions experimentally. Our final aim in this project is to offer to the scientific community extensive knowledge about the structural dynamics of these important protein targets, as well a collection of novel chemical probes ? compounds that can be used to study biological hypotheses in cells and in animal models. We hope that this work will allow significant advancements in the understanding of the biology and therapeutic potentials of EZH2 and SETDB1 in the near future. We will also address clinical mutations that have already been discovered for existing inhibitors of EZH2, and propose novel, allosteric, modes of binding with potential to lead to second generation lymphoma and melanoma therapeutics. This project will provide tools for the understanding of the epigenetics of cancer initiation and progression in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710412
Entities
People
- Rafal Wiewiora
Organizations
- United States Army
- Weill Cornell Medicine