Research team

Expertise

I have acquired strong technical abilities in the design and synthesis of organic compounds using conventional and modern organic synthesis over the last ten years of research in several institutions. Also, I have a good knowledge/experience of biological and pharmaceutical principles and a working knowledge of the use of structure-based and other computer-aided drug design tools. My research experiences resulted in a consistent track record of academic accomplishments.

Potent intra-tumoral autophagy blocking with kinase PROTACs and inhibitors. 01/11/2023 - 31/10/2025

Abstract

In tumors, autophagy acts as a survival mechanism that protects tumor cells from cytotoxic drugs and the hypoxic and nutrient-deprived tumor microenvironment. Inhibition of autophagy has been shown to increase and restore sensitivity to cytotoxic therapy and to promote tumor cell death, both in vitro and in vivo. Recently, there is also evidence that autophagy plays a critical role in tumoral angiogenesis and lymphangiogenesis. To date, only the weak, non-specific autophagy inhibitor chloroquine is clinically used in oncology. Other, more specific autophagy blockers have been reported, e.g. inhibitors of the autophagy kinases ULK1/2 and Vps34. While potent in vitro, clinical translation is difficult: obtaining reproducible autophagy inhibition in vivo is challenging with these agents. This sets the stage for this project, which aims to prepare and investigate the following 2 novel compound types: 1) ULK1/2 and Vps34 PROTACs. These compounds could be especially efficient at inhibiting autophagy because they clear ULK1/2 or Vps34 from the cytosol: this not only abrogates their kinase activities, but also additional functionality that is exerted through protein-protein interactions. 2) Tumor-selective kinase inhibitors and PROTACs. Selective delivery of autophagy inhibitors to tumors would allow both intratumoral accumulation of the molecules and reduce exposure of healthy tissue. To this end, we will prepare peptide-drug conjugates of ULK1/2 and Vps34 inhibitors and PROTACs.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

Cell-type specific delivery of autophagy inducers as a strategy to address localized autophagy impairment in disease 01/11/2023 - 31/10/2025

Abstract

Autophagy is a ubiquitous physiological process that breaks down and recycles obsolete or dysfunctional cellular components. It helps cells to survive during times of nutrient deprivation and supports clearance of protein aggregates and damaged subcellular components, thereby avoiding proteotoxic stress. Impaired autophagy has been identified as a hallmark of multiple pathologies, among others cardiovascular disease and metabolic disorders. During the last years, preclinical evidence has mounted that pharmacologically inducing autophagy, could be a game-changer in the treatment of these diseases. From a safety and efficiency perspective, one might question whether systemic treatment with autophagy inducers is the optimal way to address the localized autophagy defects that are present in most of these diseases. With that respect, we propose a cell-type specific strategy for delivering autophagy inducers. More specifically, we will prepare autophagy inducers that are chemically derivatized to target two cell types that play a key role in diseases characterized by impaired autophagy: 1) vascular endothelium (atherosclerosis) and 2) hepatocytes (NAFLD/Non-alcoholic fatty liver disease). All new compounds will be thoroughly investigated in vitro and in cells. The most promising compound will be submitted to in vivo investigation in a murine model of either atherosclerosis or NAFLD.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

Tissue-specific induction of autophagy as an innovative therapeutic strategy in cardiovascular and metabolic disease. (CARDIOPHAGY). 01/07/2022 - 30/06/2024

Abstract

Western-style diets are hypercaloric and characterized by high fat and high sugar content. They are responsible for an epidemic of cardiovascular disease, including atherosclerosis (AS), and metabolic disorders, including Non-Alcoholic Fatty Liver Disease (NAFLD). The European population is becoming increasingly exposed to these disorders, for which the only available therapeutic option is lifestyle modification. This typically involves dietary changes and physical activity, but patient compliance with these measures tends to be suboptimal. Pharmacological treatment options could therefore have significant potential to improve patient perspectives. With this respect, pharmacological induction of autophagy is intensively studied. Autophagy is the main detoxification and recycling mechanism of cells, and it has been shown to become dysfunctional in AS and NAFLD. Small molecules that can stimulate the process have been demonstrated to treat the diseases in animal models. However, all known autophagy-inducing molecules lack specificity, and this is suspected to cause systemic toxicity during chronic application in humans. In this proposal, we deliver molecules that avoid systemic exposure by targeting them specifically to disease-relevant tissues. First, potent autophagy inducers will be chemically linked to selected 'homing peptides' that we hypothesize to deliver the molecules to dysfunctional vascular endothelial cells in atherosclerosis. Similarly, we hypothesize that triantennary N-acetyl galactosamine (GN3) can guide autophagy inducers to liver cells in the context of NAFLD. All molecules that are prepared in this project will be first studied in cells: both autophagy induction potential and tissue targeting will be evaluated thoroughly. For the best molecule prepared (either endothelial- or liver-targeted), in vivo proof-of-concept will be delivered. In this way, the proposal's potential to deliver new, relevant drugs will be maximally valorized.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project