Kip Harry: | Hello. My name is Kip Harry, conference director at Cambridge Healthtech Institute, and today we have a special podcast for the upcoming Targeting the Ubiquitin Proteasome System, part of the 12th Annual Discovery on Target Conference
this October 8 to 10 in Boston. We are very excited to have one of our speakers from the event joining us via phone, Dr. Benedikt Kessler, who is a university research lecturer in the Ubiquitin Proteolysis Group, part of the Target
Discovery Institute Nuffield Department of Medicine at the University of Oxford. Benedikt, how are you today? |
BenediktKessler: | I'm fine. Thank you. Thank you. Thanks for inviting me. It's great. |
Kip Harry: | No, we're very excited to talk with you today, so let's get into it. The concept of modulating protein degradation as a therapeutic strategy, now this has been around for a while now, and we even have two proteasome inhibitors approved
in the US. So my first question for you is: what are the most present opportunities in this space? I guess another way to ask that would be: what are some of the most promising ubiquitin proteasome system targets currently being investigated
and within what indications? |
BenediktKessler: | Yes, so it's an emerging area. It's a fast-emerging area, and I think to answer that question, one of the major targets is actually the immunoproteasomes. This is a particular version of the proteasome that exists in particular immune
cells and also which is rapidly induced in the context of information, and that immunoproteasome has particular properties that make it distinct from the normal or housekeeping proteasome. There are now small molecules and probes available
that actually target particularly the function of this immunoproteasome variant, and there are elegant studies that would indicate that this can be exploited for the treatment of autoimmunity diseases such as arthritis, so that's,
in my view, one of the very interesting emerging targets. The other class of proteins or enzymes in the UPS systems are the DUBs, the D-U-Bs, or deubiquitinating enzymes. These are catalytic enzymes that, as a biological function, cleave ubiquitin or ubiquitin chains from protein substrates,
and they are considered druggable because they have all the catalytic cleft that all proteolytic enzymes have in common, which is something that the pharma industry or drug-discovery industry is using quite often for small-molecule
development. Then the third class of enzymes are the E3 ubiquitin ligases, the conjugating enzymes. Those ones are the most diverse in the class, in the ubiquitin system, but they mostly function through protein-protein interactions, which from a small-molecule
development are the most challenging ones to target. |
Kip Harry: | Benedikt, I'm going to pick up on some of the targets you mentioned, particularly the DUBs, a little later, but for right now, I just want to sort of get a broader sense of this. It seems very complex to safely modulate such a large cellular
machinery like the UPS. It seems like a very challenging task, so what are some of these challenges that have slowed the progress of generating lead molecules? |
BenediktKessler: | That is a good question because initially when people started to modulate proteasome function, the prediction was that that would never result in any type of clinical exploitation because every cell has proteasomes. If you block this activity,
you kill virtually every cell. The reality now is that there are two approved drugs, as you mentioned before, that target exactly that proteasome species, and I think the secret to this is that you don't need complete inhibition of
this activity. Partial inhibition, which may render some cells untouched, may be very sensitive to other cell types. In this case, myeloma cells, they cannot tolerate even partial inhibition of that particular enzyme species. So that
indicates one of the challenges; this is dose. How much inhibition of the enzymes do you need in order to achieve a therapeutic effect before it becomes toxic? Then, the second difficulty for the DUBs, the deubiquitinating enzymes, is that many of these enzymes have very similar catalytic-cleft properties, so it makes the drug design relatively challenging to then be able to distinguish between
individual enzymes. Then, for the third enzyme class, the E3 ubiquitin ligases or conjugating enzymes, one needs to interfere with specific protein-protein interactions, which for small-molecule and drug development is particularly
challenging to achieve in a specific manner. |
Kip Harry: | Okay, so let's get back into a little bit more of a focused discussion here, and much of your work focuses on the DUBs. As you mentioned, these are certainly of interest to drug developers, but why particularly? I know that there are several
components to the UPS that are being considered, such as the E3 ligases, et cetera, but why are DUBs emerging as such a viable therapeutic target? |
BenediktKessler: | I think that has probably two reasons. The first is that DUBs have a comfortable diversity size. There are about 100 known DUBs in the human genome, so therefore, they must have distinct cell biological functions, many of them actually
quite fundamental. I think that piece of research to understand what these individual DUBs really do in normal cell physiology and also in pathology is still ongoing, so this means you can tailor or influence specific events by targeting
particular DUBs that have distinct substrates or distinct functions without touching the rest. Then the second reason is that, as I said before, they are druggable targets. Most of them are cysteine protease types, so they have a catalytic triad which functionally and also structurally can offer quite a good scaffold for small-molecule
inhibitor development. So the combination of the two makes, I think, this type of enzyme class very attractive therapeutic targets. |
Kip Harry: | Mm-hmm. Picking up on your expertise within this space, what are the challenges that are unique to targeting DUBs as opposed to the PPIs of ubiquitin ligases? |
BenediktKessler: | Yes. I think the first major challenge is that many of these DUBs, although they do different things, the catalytic triad where the actual action of the enzyme happens seems to be quite similar in many of these enzyme classes, so if one
aims to inhibit a particular DUB over others, the challenging part is to find out what the fine specificities, particularly on a structural basis, are that could be exploited for specific small-molecule inhibitor design. That has been
quite challenging and requires the acquisition of much more structural information that can then be compared to tease out differences that can then be exploited for small-molecule development. |
Kip Harry: | I'm assuming that this sort of unlocking the target space of these DUBs has some sort of technological component to it. What are some of the novel tools and technologies that are being developed or implemented, and perhaps even in your
own lab, to overcome some of these challenges? |
BenediktKessler: | That's a very good question, and this probably represents quite a bit of effort that is ongoing in many different labs, also in different pharmaceutical companies. What is simply required is to make, of course, these DUBs in recombinant
forms to study them biochemically, biophysically, and also for inhibition assays. What our lab or what my lab can contribute to this in particular is the ability to study the function and also activity of these DUBs in a cellular environment. So we have, for example, developed specific activity-based probes, molecular probes, which are based on the ubiquitin scaffold, and through chemical trick can track and trap these active DUBs in cells or in a cellular environment. We can
use this in combination with a chemo-proteomic approach to actually isolate and display the active profile of all DUBs or most DUBs in the cell. Now, this is quite important because it gives us a snapshot of how active these DUBs really
are in a cellular environment, which is something that is currently lacking in most of the labs and also industry approaches worldwide. So that's what we can bring from my lab on the table to accelerate this drug development in that
direction. |
Kip Harry: | Mm-hmm. Let's get into a bit more about your lecture. You're giving an actual lecture at the 12th Annual Discovery on Target Conference this October 8 to 10 in Boston during this very focused meeting targeting the ubiquitin proteasome
system. What do you hope to convey to attendees during your lecture? |
BenediktKessler: | First of all, I'm delighted that I can participate in that meeting. That is great. What I would like to do or take the opportunity to do in this context is to demonstrate the importance of DUBs as novel therapeutic targets not only for
cancer ... there's a particular focus on cancer in many of these programs going on at the moment ... but also in other disease types such as neurodegeneration, but also immunity, in particular, infectious diseases because there are
pathogens that actually encode for endogenous proteolytic enzymes that have DUB-like properties. This is something that can be pharmacologically exploited, as well, for novel antiviral or antibacterial drugs in the future. So I think
this, with the concept of really tracking the DUBs enzyme in a cellular environment through our approaches that we have in the lab is something that I would like to present in that meeting. |
Kip Harry: | Mm-hmm. You mentioned the intensity of work being done in oncology, but we certainly do actually have a session during the meeting that's focused on other indications in chronic disease, so that's on the program, as well. I think I would
like to go ahead and wrap this up, but before I do that, we always like to end these podcasts with an outlook. I think this is probably the hardest question I could ask you, but in your opinion, what is on the horizon for research
in this space? I guess another way to ask that is what are the future goals that need to be accomplished to really push these novel medicines further into the clinic? |
BenediktKessler: | Yeah. I think the first challenge is that there is probably about 10% of all genes in the human genome that somehow have to do with ubiquitin, so in that sense, the ubiquitin proteasome system is actually covering a vast amount of targets
that can be exploited, so I think that's the first. The space is actually quite large. To push that forward towards novel medicine that can be pushed into the clinic, I think it's important that we can move rapidly from the discovery of lead compounds for particular DUBs that can be further optimized in SARs and then put
it towards what I would call in vivo models, some particular cell-culture models, but also mouse tumor or other pathology models to rapidly test out which inhibitors, which DUB targets are actually worthwhile going forward, pushing
further. Then I think the third part is to think quite rapidly about combination therapies, so to try at the very early stage, try to mix that, say, potential DUB inhibitors with other type of drug compounds, for example, the proteasome inhibitors
or other small molecules that work through a different mechanism that can be completely off [inaudible 00:11:49]. So this potential combination of therapies, in my view, is the future, and this includes probably the combination of
UPS-based targets with other types of targets outside of that system. |