Research

Development of novel Hsp90 inhibitors with anticancer activity

Code:

J1-1717

Range:

01. January 2019 - 30. June 2023

Range:

0,83 FTE

Leader:

Tihomir Tomašič

Field:

1-09 Natural sciences and Mathematics - Pharmacy

Abstract:

Scientific background and problem identification. Despite considerable improvements in treatment and survival times, cancer still remains one of the leading causes of mortality worldwide. Therefore, there is an urgent need to identify new drugs acting on new targets to improve treatment outcomes, especially against some aggressive types with no standard therapies, such as some non-Hodgkin lymphoma subtypes. Since chaperones are key players in maintaining a balanced protein homeostasis and several types of cancer are characterised to some extent by misregulated proteostasis, heat shock protein 90 (Hsp90) chaperone represents important new target for anticancer drug development. Hsp90 is overexpressed in many different types of cancer and modulates the conformation of around 300 proteins, many of which are directly associated with cell signalling, and thus, are often hijacked during malignant transformation. Consequently, through Hsp90 inhibition, multiple signalling pathways can be disrupted simultaneously, which leads to potent anticancer effects. State-of-the art. Since discovery of the natural product geldanamycin as Hsp90 inhibitor, twenty Hsp90 inhibitors have undergone clinical investigation against different types of cancer. Unfortunately, all of these molecules bind to the Hsp90 N-terminal domain (NTD), and also induce the pro-survival heat shock response at the same concentration they inhibit the Hsp90 protein folding machinery. The net result is generally, cytostatic activity and the potential for chemotherapeutic resistance. Unlike NTD inhibitors, C-terminal domain (CTD) inhibitors can segregate these activities, which have led to unforeseen opportunities for the development of useful anticancer agents. In fact, CTD inhibitors do not induce the heat shock response and consequently, induce apoptosis against many cancer cells with high differential selectivity. Most of the known Hsp90 CTD inhibitors are analogues of the aminocoumarin antibiotic novobiocin developed by the group of Prof. Blagg, who is the partner of the project consortium. Project objectives. The scientific objective of the project is to develop new anticancer leads targeting the emerging cancer target Hsp90 CTD as a new approach to treat cancer. We aim to identify new structural class of potent and selective Hsp90 CTD inhibitors against lymphomas and selected solid tumours that do not induce the heat shock response by hit-to-lead optimisation of starting in-house compounds and virtual screening hits. In addition, we will prepare first proteolysis targeting chimeras (PROTACs) by conjugating identified Hsp90 inhibitors with E3 ligase ligands to study Hsp90 degradation in cancer cells. Work programme and implementation. The project covers the full cycle of early stage lead discovery process, including computer-aided design, medicinal chemistry, molecular target screening and profiling of anticancer activity and is organised in five interconnected work packages (WP). The overarching aim of the project will be realised by several specific tasks in each WP that will be performed by the group of project leader Assoc. Prof. Dr. T. Tomašič at the University of Ljubljana, Faculty of Pharmacy, group of Prof. S. Golič Grdadolnik at National Chemistry Institute, Slovenia (KI), and three foreign partners: group of Prof. B. Blagg at the University of Notre Dame, USA, group of Dr. A. Zubriené at the Vilnius University, Lithuania, and group of Dr. E. Gaudio at the Institute of Oncology Research, Switzerland. The expertise of the project partners is complementary and synergistic and they have experience and necessary equipment for successful realisation of the project objectives. Moreover, they have already established collaboration, which is an added value that guarantees the progress and success of the project – development of novel potent and selective Hsp90 CTD inhibitors active against lymphomas and selected solid tumours.