Cancer Drug Development

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. More recently, we published the first fully characterized highly selective HDAC10 inhibitor chemical probes. Currently, our work is focused on the synthesis of HDAC10 PROTACs and the use of these compounds to better understand HDAC10 biology and its potential as a therapeutic target in cancer.

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.

We have accumulated extensive expertise in the synthesis and characterization of bifunctional degraders (e.g. PROTACs) over the past decade. Currently we are working on four different degrader projects, including HDAC10 PROTACs, but these projects have not yet been made public.