AIRC IG 2016 Id 18776 "The CtBP1/BARS involvement in tumor progression: a specific target for pharmacological intervention" (DSB.AD001.093)

Thematic area

Biomedical sciences

Project area

Structure responsible for the research project

Istituto di Biochimica e Biologia Cellulare (IBBC)

Project manager

DANIELA CORDA
Phone number: 0816132536
Email: d.corda@ibp.cnr.it

Abstract

CtBP1/BARS, identified by us as an essential component of the membrane fission machinery, belongs, with CtBP2 and
RIBEYE, to the C-terminal binding (CtBP) protein family. CtBP1/BARS is bifunctional: it acts to control membrane fission in
membrane transport and in mitotic Golgi partitioning. Inhibiting the latter blocks G2-M transition and causes apoptosis. It also
acts in the nucleus to repress transcription of genes with proapoptotic, tumor-suppressor and other cancer-relevant functions.
The CtBPs play important roles in promoting major cancers. Structurally, the CtBPs
belong to the 2-hydroxyacid dehydrogenase superfamily and have a Rossman fold that determines their conformation
and function, depending on the ligand (e.g., NADH or acylCoA or synthetic molecules) it binds to.
The central idea here is that the CtBPs Rossman fold is a potential pharmacological target for cancer therapy.
We now propose the idea to develop molecules with high selectivity and affinity for the Rossman fold in
CtBP1/BARS and CtBP2 and with drug-like properties; and to characterize their effects in models of human cancers, with the
aim to generate molecules suitable for clinical testing.

Goals

AIRC IG 2016 Id 18776 "The CtBP1/BARS involvement in tumor progression: a specific target for pharmacological intervention"

This project has two aims. While the molecular role of CtBP in transcription is known, the mechanism of CtBP-driven
membrane fission needs clarification. The first aim is to elucidate this mechanism and especially the role of lipid-modifying
enzymes in mitotic Golgi partitioning in order to rationally design CtBP Rossman fold ligands that block G2-M transition
causing apoptosis and/or the CtBP transcriptional pro-tumoral effects. The second and central aim is to generate CtBP Rossman
fold ligands endowed with drug-like properties and sufficient potency and selectivity in specific cancer models (when
administered individually or in combination with chemotherapy agents) to become good candidates for clinical testing.

Start date of activity

02/01/2017

Keywords

Membrane biology, Drug discovery and/or development, Mitosis-Golgi

Last update: 18/04/2024