Projects

HDAC10 Inhibitors

Histone deacetylases are a group of hydrolase enzymes which are responsible for the removal of acyl groups primarily from lysine residues on proteins, but also from other acylated amine metabolites. HDAC10, for example, is known to be a poor lysine deacetylase but an efficient polyamine (e.g. spermidine) deacetylase. Furthermore, a number of studies have highlighted HDAC10 as a potential cancer drug target: (1) High HDAC10 expression levels were found to correlate with poor clinical outcome for advanced stage 4 neuroblastoma patients who received chemotherapy. (2) Consistent with these findings, HDAC10 depletion in neuroblastoma cells interrupts autophagic flux and sensitizes cells for chemotherapy, and enforced HDAC10 expression protects neuroblastoma cells against doxorubicin treatment.

We have published the first systematic investigations into the development of HDAC10 inhibitors and have found that a number of putatively selective HDAC6 inhibitors are also very good HDAC10 inhibitors. Indeed, we found that tubastatin A, one of the best-known HDAC6 inhibitors, is an even better HDAC10 binder (see Publications page). We have established two ligand-displacement assays which enable the accurate measurement of HDAC10 binding, both with recombinant protein and in cells. Currently, our work is focused on the synthesis of novel selective HDAC10 inhibitors and HDAC10 PROTACs and using these compounds to better understand HDAC10 biology and its potential as a therapeutic target in cancer.

This graphic shows a model of tubastatin A binding to HDAC10 and making a hydrogen bond to the gatekeeper residue, Glu272. Derivatization of the tubastatin A scaffold reveals that an appropriately positioned basic nitrogen atom in the cap group is required for selectivity over HDAC6.

KLK6 Inhibitors and Activity Probes

Kallikrein-related peptidases (KLKs) are a family of 15 secreted serine proteases that have been shown to play a role in a variety of pathological conditions. Largely investigated as biomarkers, it is now becoming increasingly clear that KLKs also have a direct role in disease progression. KLK6, for example, has been shown to promote migration and invasion of tumor cells in melanoma and colon cancers, but few reports of KLK6 inhibitors have been made in the literature.

We have recently described a novel series of depsipeptides which are covalent inhibitors of KLK6. After a thorough investigation of the SAR and MOA of these substances, we converted them into activity probes by the introduction of an alkyne handle. These probes could then be used to pull-down endogenous KLK6 from cell lines and enable a first estimation of enzymatic activity in biological samples.

Current work aims to improve these inhibitors/probes and develop a reliable diagnostic method to measure KLK6 activity in human samples.

DKFZ-251 covalently modifies the active site Ser195 of KLK6 and shows cellular activity that phenocopies KLK6 knockdown. DKFZ-633, an activity probe based on the DKFZ-251 scaffold, enables pull-down of active KLK6 from cancer cells.

TRXR1 Inhibitors

MetAP2 Inhibitors

Methionine aminopeptidase 2 (MetAP2) is one of two redundant enzymes that cleaves the starter methionine from proteins as part of their maturation process. MetAP2 is overexpressed in many cancers, and selective inhibition of MetAP2 results in reduced vascularization and growth of tumors. Furthermore, MetAP2 has been shown to play a role in fat production and is investigated as an anti-obesity target.

Many covalent MetAP2 inhibitors are semi-synthetic substances that are derived from the natural product fumagillin. Aiming to discover novel, drug-like, covalent MetAP2 inhibitors, we have developed a synthetic route to access novel fumagillin-inspired compounds which are potent, selective, and cellularly active MetAP2 inhibitors.

Spiroepoxides, inspired by the structure of fumagillin, are good inhibitors of the enzyme MetAP2.

PROTACs

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