PRIN2020 Bergamaschi (DCM.AD007.251)
Thematic area
Chemical sciences and materials technology
Project area
Chimica e materiali per la salute e le scienze della vita (DCM.AD007)Structure responsible for the research project
Istituto di Scienze e Tecnologie Chimiche "Giulio Natta" (SCITEC)
Project manager
GRETA BERGAMASCHI
Phone number: 0228500026
Email: greta.bergamaschi@cnr.it
Abstract
Our goal is to develop a strategy integrating computation, synthesis, molecular and cell biology in vitro and in vivo, to design molecules for the selective perturbation of TRAP1 activity and interactions in cancer cells and their microenvironment. We have built a structure-dynamics-activity approach that led to the identification of potent and effective (in vitro and in vivo) TRAP1-selective hits. In this project, we will advance molecular design strategies based on the analysis of functional protein dynamics and interaction surfaces, and will merge them with synthetic methods to deliver innovative chemical tools. The latter will be probed in models of tumors associated with the genetic syndrome neurofibromatosis type 1 (NF1), and in diffuse large B cell leukemia (DLBCL), for which no treatment exists. We will use cultured cells and murine tumor models to determine if TRAP1-targeting compounds affect the enzymatic activity of TRAP1, SDH, ERK, CyP-D, F-ATP synthase; their expression level and interaction dynamics; the viability and tumorigenicity of cells; macrophage recruitment, differentiation and their feedback effects on tumorigenicity.
Goals
1. Design and optimization of active hits as allosteric regulators of TRAP1 activities
2. Develop methods and chemical tools to perturb TRAP1 interactions
3. Analyse the biochemical and biological effects of TRAP1-targeting compounds on NF1 and DLBCL tumor
cells
4. Investigate TRAP1 role in tumor associated macrophages
5. In vivo studies of tumor growth inhibition by TRAP1-selective hits
We expect to advance the candidates for NF1 and DLBCL treatment toward preclinical studies. In doing so,
we will advance our fundamental knowledge on the design of chemical regulators of cell biology.
Start date of activity
01/03/2022
Keywords
molecular design, organic chemistry, molecular biology and interactions
Last update: 19/04/2024