The molecular mechanisms that instigate a healthy cell to become malignant are fueled by (epi)genetic alterations in so-called driver genes.

Inactivating mutations in BRCA1 or BRCA2 genes predispose to several types of cancer.

Large parts of the research described in this Thesis aims at the development of oligopeptide-masked toxins and their in situ immunoproteasome-mediated activation.

Promotores: Prof.dr. H.S. Overkleeft, Prof.dr. G.A. van der Marel

The disease acute myeloid leukemia (AML) is characterized by fast progression and low survival rates.

Promotor: H.S. Overkleeft, J. Neefjes, Co-promotor: M. van der Stelt

Less than 1 in 10 drug candidates that enter phase 1 clinical trials actually gets approved for human use.

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This Thesis describes the design, synthesis and evaluation as glycoprocessing enzyme inhibitors of focused libraries of iminosugars.

Promotores: H.S. Overkleeft, G.A. van der Marel, Co-Promotor: J.D.C. Codee

Glycosidases are essential in fundamental biological processes and are responsible for the degradation of most (oligo)saccharides, glycolipids and glycoproteins.

The research described in this thesis focused on identifying novel drug targets and synergistic combinations for triple-negative breast cancer (TNBC), a virulent subtype of breast cancer with a dismal prognosis and limited therapeutic options.

Phosphorylation affects all four major biomolecules – proteins, lipids, carbohydrates and nucleic acids – and plays a pivotal role in the most fundamental cellular functions.

Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt

This thesis describes the design and development of subunit‐selective inhibitors of particular catalytically active subunits of human constitutive proteasomes and immunoproteasomes.

Promotor: Prof.dr. J.P. Abrahams, Co-Promotor: N.S. Pannu

Promotores: B. van de Water; P. Hogendoorn; J. Bovée Co-Promotor: E.H.J. Danen

The studies presented in the work show the potential of the integrative use of biophysical data in defining the structural basis of protein interactions.

To this day, all cyclophellitol-based inhibitors and ABPs have been close analogues of their natural substrate counterparts. As a result, these probes showed high selectivity towards their target glycosidases.

Promotores: H.S. Overkleeft; G.A. van der Marel Co-Promotor: B.I. Florea

Promotores: Prof.dr. H.S. Overkleeft, Prof.dr. G.A. van der Marel

Tijdens de Dutch Medicine Days viel het Leiden Academic Centre for Drug Research (LACDR) maar liefst drie keer in de prijzen. Bas Goulouze won de PhD Prize voor beste promovendus, Natalia Ortiz Zacarías en Huub Sijben mochten beiden een posterprijs in ontvangst nemen. 'Wetenschappers moeten in staat…

Glycosidases are important enzymes in the turnover of polysaccharides and glycoconjugates, and are involved in a range of human pathologies including genetic disorders such as Gaucher and Pompe disease, but also in various cancers.

Drug development is a time- and resource-consuming process that starts with the discovery and validation of a (protein) target that contributes to pathogenesis or disease progression.

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Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt

BlaC is the β-lactamase of Mycobacterium tuberculosis. We show that it can recover from inhibition by clavulanic acid and that phosphate helps it do so.

Due to their central physiological roles in living organisms, retaining beta-glycosidases have been the subject of tremendous research efforts to examine their structure/function relation using numerous biophysical and biochemical approaches.

In this thesis, the discovery and optimization is described of chemical tools to study the N-acylethanolamine (NAE) biosynthetic pathway.

Promotor: H.S. Overkleeft, Co-Promotor: B.I. Florea

Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt

This thesis describes the structural and biochemical characterization of the β-lactamase BlaC from Mycobacterium tuberculosis (Mtb), and the Alr and YlmE proteins from Streptomyces coelicolor A3(2).Mtb is the main cause of tuberculosis.

In this thesis, a system pharmacology approach, integrating metabolomics, pharmacology and chemical biology, was applied to understand and modulate the endocannabinoid system across different model systems (cells, zebrafish, mice and humans).

Lysosomal glycosidases are acid hydrolases that fragment glycoconjugates in lysosomes.

In the last decades, activity-based protein profiling (ABPP) has emerged as a powerful chemical tool that may aid the ever-challenging drug discovery process.

Promotor: Prof.dr. J. Kuiper

In this thesis, we used genetically engineered mouse models to identify genes and pathways that are involved in ILC formation and in the development of resistance to FGFR-targeted therapy.

Promotor: Prof.dr. H.S. Overkleeft

Freek Janssen kreeg tijdens de FIGON Dutch Medicine Days 2015 op 5 oktober in Ede de KNCV Farmacochemie prijs voor beste presentatie uitgereikt. Janssen ontvangt deze prijs voor zijn presentatie "Discovery and optimization of highly selective and reversible diacylglycerol lipase inhibitors".