Research

Preclinical development of mitochondrial chaperone TRAP1 inhibitors as anticancer agents

Code:

J1-70043

Range:

01. March 2026 - 28. February 2029

Range:

1.10 FTE

Leader:

Tihomir Tomašič

Field:

1-09 Natural sciences and Mathematics - Pharmacy

Abstract:

Despite significant improvements in treatment and survival rates, cancer remains one of the leading causes of death worldwide. Therefore, there is an urgent need for new drugs that act on novel targets to improve treatment outcomes, particularly against some aggressive cancers for which there are no standard therapies. The MitoTRAP (Preclinical development of mitochondrial chaperone TRAP1 inhibitors as anticancer agents) project aims to expand the target range of anticancer drugs through the rational design of inhibitors of the mitochondrial chaperone tumour necrosis factor receptor-associated protein-1 (TRAP1).

Reprogramming of metabolic pathways in mitochondria is a hallmark feature of cancer that plays a crucial role in disease progression and highlights the potential of mitochondria as a unique therapeutic target for cancer. Mitochondria in cancer have a unique ”wiring” compared to normal tissue, potentially providing a broader therapeutic window. Most cancers are characterised by impaired protein homeostasis and exhibit an increased dependence on heat shock proteins. In fact, Hsp90 family chaperones are overexpressed in many cancers. TRAP1 is a member of the Hsp90 family in the mitochondria. Its physiological functions in normal cells are still poorly characterised. However, several studies have highlighted the crucial role of TRAP1 in reprogramming mitochondrial metabolic pathways to critically support tumour growth, making TRAP1 a promising target for anticancer drug development.

All inhibitors of the Hsp90 family studied clinically to date suffer from non-selective inhibition of all four isoforms (Hsp90α, Hsp90β, Grp94 and TRAP1), leading to induction of pro-survival heat shock response (HSR) and to overall client destabilisation, which may lead to toxicity and prevent further progress in therapeutic application. The overall goal of the MitoTRAP project is to develop selective TRAP1 inhibitors that do not induce HSR to circumvent the drawbacks of the known Hsp90 family inhibitors. We also aim to develop innovative, tailored mitochondria-targeting moieties (MTMs) that not only serve to deliver the compounds into the mitochondria, but also interact specifically with TRAP1 (Objective 1). To date, the triphenylphosponium (TPP+) cation is the most commonly used MTM. Although there are no reports of serious toxicity of TPP+ conjugates in vivo, recent studies have shown that the TPP+ moiety has deleterious effects on mitochondrial bioenergetics. Therefore, we aim to develop safer pyridinium-based MTMs and conjugate them with TRAP1 inhibitors of the N-terminal (Objective 2) and C-terminal domains (Objective 3) to achieve selective accumulation of the inhibitors in mitochondria and potent anticancer activity with minimal side effects. In addition, we aim to develop new inhibitors of TRAP1 holdase function (Objective 4) that bind to the TRAP1 middle domain and thus achieve anticancer activity by a novel mode of action.

The interdisciplinary MitoTRAP project covers the full cycle of early-stage lead discovery, including computational design, medicinal chemistry, in vitro and in vivo profiling of cancer activity, and is organised into three interrelated scientific and two communication and management work packages (WPs). The overall goal of the project will be achieved through several specific tasks in each WP, carried out by the group of Dr Tomašič at the University of Ljubljana, and two partners: the group of Dr Golič Grdadolnik at the National Institute of Chemistry, Slovenia, and the group of Dr Sturtzel at the Children's Cancer Research Institute, Austria. The expertise of the project partners is complementary and synergistic, and they have the experience and the necessary equipment for the successful implementation of the project overarching goal: Development of innovative TRAP1 inhibitors as preclinical leads for the treatment of cancer.