AIRC COLOMBO 2015-2017 (DCM.AD007.018)

Thematic area

Chemical sciences and materials technology

Project area

Structure responsible for the research project

Istituto di Scienze e Tecnologie Chimiche "Giulio Natta" (SCITEC)

Project manager

GIORGIO COLOMBO
Phone number: 0228500031
Email: giorgio.colombo@icrm.cnr.it

Abstract

The Hsp90 chaperone family, which includes the paralogs Hsp90, Grp94 and Trap1, is differentially expressed in cancer where it orchestrates multiple signaling pathways essential for tumor cell viability and proliferation. While the therapeutic relevance of Hsp90 is recognized, the specific role of individual paralogs in cancer development is poorly understood. Recent evidence shows that the expression levels and functions of each paralog can indeed depend on the tumor type and grade.
Aims
This project aims to discover small molecules able to perturb specific Hsp90 cell functions by allosteric modulation of functional motions. We will focus on integrating computational biology with medicinal chemistry and experimental biology to translate the mechanistic understanding of the functional dynamics of Hsp90 paralogs into 1) the optimization of existing active anticancer compounds; 2) the development of chemical tools able to selectively target paralogs in their cellular contexts; and 3) the characterization of ligand effects on Hsp90-protein interactions.

Goals

(1) improve our understanding of ligand-dependent allosteric and interaction mechanisms in Hsp90 family members; (2) optimize existing and develop new anticancer drugs aimed at perturbing Hsp90 functions avoiding side effects related to ATP-site targeting; (3) generate paralog-specific effectors as chemical tools to investigate the links between the activities of individual paralogs and their biological roles. We will test the activities of the designed allosteric molecules in different experimental biochemical/biophysical settings and against a wide range of human cancer models, so that at the end of our studies, we will have sufficient data to support preclinical evaluations. We will also evaluate the effects of their co-administration with geldanamycin (or other drugs) to parental and geldanamycin-resistant tumor cells to investigate possible synergistic effects as well as the ability of new compounds to overcome resistance. At the end of the project, we expect to deliver at least 5 candidates to enter in vivo testing.

Start date of activity

02/01/2015

Keywords

Chaperones, drug design, molecular dynamics

Last update: 27/04/2025