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| Group Leader in Chemical Proteomics, Dr. Guillaume Médard, and his research group in the lab. Credit: Uli Benz / TUM |
Scientific Frontline: Extended "At a Glance" Summary: Chemical Proteomics and HDAC Inhibitor Profiling
The Core Concept: Mass-spectrometry based chemical proteomics is a big-data analytical approach used to simultaneously monitor thousands of proteins, allowing researchers to discover the precise protein targets and unintended off-targets of small molecules like histone deacetylase (HDAC) inhibitors.
Key Distinction/Mechanism: Unlike conventional targeted assays that monitor single protein-drug interactions, chemical proteomics utilizes target deconvolution and customized affinity matrices to systematically profile a drug's binding activity across the entire proteome at once.
Major Frameworks/Components:
- Mass-Spectrometry Based Proteomics: The big-data science utilized to monitor the abundances of thousands of proteins simultaneously within a sample.
- Target Deconvolution: A method using newly developed affinity matrices to systematically profile drug interactions and identify the actual proteins engaged by small molecules.
- Epidrugs (HDAC Inhibitors): A specific class of oncology drugs designed to target and inhibit histone deacetylases.
- MBLAC2: A previously obscure protein identified as an unintended off-target for approximately half of the profiled HDAC inhibitors.
- Extracellular Vesicles (Exosomes): Small, membrane-bounded particles responsible for transmitting biomolecules between cells, which accumulate in the extracellular space when MBLAC2 is inhibited.
Branch of Science: Proteomics, Pharmacology, Biochemistry, and Molecular Biology.
Future Application: The data will guide medicinal chemists in designing more selective epidrugs and specific MBLAC2 inhibitors, enabling advanced studies of exosome biology in neurological, immunological, and oncological models.
Why It Matters: This study highlights that many widely used oncology drugs are far less selective than previously assumed. It provides a crucial dataset for researchers to select the most precise chemical tools and uncovers a novel biological mechanism regulating cellular communication via extracellular vesicles.
Histone deacetylase (HDAC) inhibitors are a class of drugs used in oncology. An international research team involving scientists at the Technical University of Munich (TUM), Cornell University in Ithaca (USA), the German Cancer Research Center (DKFZ) in Heidelberg and Martin Luther University of Halle-Wittenberg has now investigated the effects of some HDAC drugs in more detail. The scientists wanted to know whether those epidrugs engage proteins other than the HDACs which they are designed to inhibit.
“To do so, target deconvolution by chemical proteomics is the method of choice. Hence, we first made new chemical tools - the so called affinity matrices - that would allow us to systematically profile the HDACs,” explains Dr. Guillaume Médard, group leader for chemical proteomics at the TUM chair of Proteomics and Bioanalytics led by Prof. Bernhard Küster.
“I profiled 53 drugs”, details Severin Lechner, doctoral candidate at the TUM School of Life Sciences. “Most of them, but not all, hit their intended HDAC target. However there were some surprises. 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 proteomic approaches that probe the binding to thousands of proteins at once. Finally, several molecules with outstanding selectivity were identified, making them HDAC inhibitors of choice for future scientific studies.
“The most unexpected finding was that MBLAC2 is an off-target of half of the profiled molecules,” Lechner continues. This protein is not well characterized but coincidentally, the team of Prof. Maurine Linder in Cornell researched on it at the same time. The two groups in Germany and the USA collaborated and confirmed that the protein is indeed hindered to perform its function in presence of the drugs.
With the group of Prof. Michael Pfaffl at TUM, hinted by unexplained phenotypic effects of some drugs, Lechner proved that MBLAC2 inhibition or knock down leads to accumulation of extracellular vesicles in the extracellular space. Extracellular vesicles are small membrane-bounded particles secreted by cells and transported through the whole body to transmit biomolecules and information between cells and tissues.
“We are excited because we uncovered a new player in this field of biology that notably encompasses 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 whomever wants to use HDAC inhibitors for probing biology or for therapeutic use. It helps choosing the right chemical tool. It is also a valuable set of data for medicinal chemists that need to understand how chemical structures relate to potency and selectivity to make tomorrow’s epidrugs.
Published in journal: Nature Chemical Biology.
Title: Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target
Authors: Severin Lechner, Martin Ian P. Malgapo, Christian Grätz, Raphael R. Steimbach, Agnes Baron, Patrick Rüther, Simon Nadal, Carmen Stumpf, Christina Loos, Xin Ku, Polina Prokofeva, Ludwig Lautenbacher, Tino Heimburg, Vivian Würf, Chen Meng, Mathias Wilhelm, Wolfgang Sippl, Karin Kleigrewe, Josch K. Pauling, Karl Kramer, Aubry K. Miller, Michael W. Pfaffl, Maurine E. Linder, Bernhard Kuster, and Guillaume Médard
Source/Credit: Technische Universität München
Edited by: Scientific Frontline
Reference Number: chm062922_01
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