Histone deacetylase (HDAC) inhibitors are a class of drugs used in oncology. An international research team involving scientists from the Technical University of Munich (TUM), Cornell University in Ithaca (USA), the German Cancer Research Center (DKFZ) in Heidelberg and the University Martin Luther of Halle-Wittenberg has now studied the effects of certain HDAC drugs in more detail. The scientists investigated whether these epidrugs affected proteins other than the HDACs they are thought to inhibit.
“To do this, target deconvolution by chemical proteomics is the method of choice. We therefore first created new chemical tools – the so-called affinity matrices – which would allow us to systematically profile HDACs”, explains Dr Guillaume Médard, group leader for chemical proteomics at the TUM chair of proteomics and bioanalysis led by Professor Bernhard Küster.
Profiling of HDAC drugs by chemical proteomics
“I profiled 53 drugs and most of them, but not all of them, met their HDAC target,” said Severin Lechner, PhD student at TUM School of Life Sciences. “However, there were a few surprises. The drugs used in hundreds of scientific studies were not as selective as assumed. Many had additional targets that were not previously known.
These results highlight the power of proteomics approaches, as they can probe binding to thousands of proteins at once. Finally, the team identified several molecules with exceptional selectivity, making them the inhibitors of choice for future scientific studies.
The target landscape of HDAC drugs
“The most unexpected finding was that MBLAC2 is off-target for half of the profiled molecules,” continues Lechner. This protein is not well characterized. Coincidentally, Professor Maurine Linder’s team at Cornell researched this at the same time. The two groups collaborated and confirmed that the protein is indeed hampered in performing its function in the presence of the drugs.
In collaboration with Professor Michael Pfaffl’s group at TUM, Lechner investigated the unexplained phenotypic effects of certain drugs and proved that inhibition or knockdown of MBLAC2 leads to an accumulation of extracellular vesicles in the extracellular space. Extracellular vesicles are small membrane-bound particles secreted by cells and transported throughout the body to transmit biomolecules and information between cells and tissues.
Basic research to manufacture the epimedicines of tomorrow
“We are delighted because we have discovered a new player in this field of biology which notably includes exosomes, which play crucial roles in neurology, immunology and oncology”, explains Médard. “We are now designing molecules that only hit MBLAC2 so that we can probe this obscure protein in a range of model systems. »
This study will be useful to those who wish to use HDAC inhibitors for probing biology or for therapeutic purposes. It helps to choose the right chemical tool. It is also a valuable dataset for medicinal chemists who need to understand how chemical structures relate to potency and selectivity to manufacture the epidrugs of tomorrow.
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Materials provided by Technical University of Munich (TUM). Note: Content may be edited for style and length.