Prof. Jonathan Baell of “PAINS” Filters Fame from Monash University

“People are just finding compounds with a bit of activity and really publishing screening hits as though they are genuine optimizable candidates. And these things can be subversive and they can look real, so these publications are kind of getting accepted and unfortunately there’s a lot of noise out there, a lot of pollution, and this is one of the things we certainly strive to do here is not to publish something for the sake of publishing, but to publish it after making optimizations showing these are absolutely real.”


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Professor Jonathan Baell

Leading Australian medicinal chemist and Larkins Fellow, Professor Jonathan Baell, has joined the Monash Institute of Pharmaceutical Sciences (MIPS) in 2012. Before his appointment to the University, Professor Baell was based at the Walter and Eliza Hall Institute where he played a central role in establishing and leading a first class medicinal chemistry group.

Dr. Baell has a range of research interests including the discovery of new anti-parasitic compounds for the treatment of malaria and neglected diseases, the design and synthesis of peptidomimetics and the development of selection criteria for quality high-throughput screening.

Interviewed by Barry Bunin, CEO Collaborative Drug Discovery, Inc.

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Edited Interview Transcript

 

Barry Bunin

I wanted to start with a more general question because the last time I saw you was at this ICBS, International Chemical Biology Society meeting in Kansas.

 

Jonathan Baell

Kansas, that’s right.

 

Barry Bunin

I thought someone looking at it from Australia, you might be able to comment somewhat impartially on the efforts going on in the U.S., Europe, and Asia. I’m curious about what you think about the developments in terms of the global efforts for drug discovery, the sort the coordination that’s been happening, and how that’s been evolving from your perspective.

 

Jonathan Baell

From my perspective, it’s really a very exciting, very exciting time. It seems to be absolutely the case that the notion, started a few years ago, that Pharma were decreasing discovery internally, and that that could therefore be a potential to present opportunities to academic institutes, really does seem to be the case. And so I’m sure there’s no major university possibly anywhere in the world now that isn’t in some active discussion or hasn’t already signed up in some partnership with Pharma, and that’s certainly the case with us at Monash University, Monash Institute of Pharmaceutical Sciences. We’ve signed up with Servier, a French drug company, and it just seems to make complete sense. They can offer complimentary skills and resources perhaps in downstream drug discovery whereas they often see the academic institute as attractive places where they feel government funds have essentially already leveraged a fair bit of research, and so then maybe they can take a few risks with earlier investing in early biology than normally they would have. So, that’s definitely turned out to be a global development, which is very good. And I think, in academia, all of us are benefitting by it really.

 

Barry Bunin

Chris Lipinski, on our SAB, initially introduced me to you right after your influential J. Med. Chem. publication on the PAINS filters and then you did a guest blog, which has been one of our most widely read guest blogs on the topic…

 

Jonathan Baell

Fantastic.

 

Barry Bunin

…as it relates to the currency in our field with patents. So, I’m just curious, how has that paper impacted the field and why did it hit a nerve?

 

Jonathan Baell

Well, that’s a good question. I was just on the guest blog. Actually, I had a lot of fun doing that and it was an opportunity to go into some practical operational aspects of how you read the filters, and how you interpret them. In the blog, there are options to do that where there wasn’t such an opportunity to do with any of the subsequent publications. So I’m actually kind of pleased to hear that was a favorite.

The PAINS paper… Well, it has absolutely hit a nerve and the timing was just right. We had been one of the earlier starters of our HTS follow-up from an Academic HTS Library and that was at the Walter and Eliza Hall Institute in Melbourne. That first started around 2002, we started assembling the library, and I think there were possibly only a couple of other institutes worldwide who were doing something similar. Possibly none doing it in the way we were doing it. Nevertheless, after cumulative years of HTS campaigns, we kept coming up with these compounds where they weren’t exactly the same compound, but they kind of looked similar and they never went anywhere. This relates obviously to this PAINS paper where eventually I just said look, there’s got to be a way of formulating these into a class, a sub-structural class, that people can recognize and they realize it’s not just one particular analog, but anything that is associated with a certain class is generally bad news. So we published this in 2010, and I suspect it must have been the case worldwide that by then there were dozens and dozens of HTS labs probably doing screening and having done so for a couple of years and it just hit a nerve. I think they must have been seeing these things, these circles of interference compounds (or PAINS, as we called them) and they were just able to instantly recognize that: wow, these are the things that have been causing the problem. So, it really had almost instantaneous take-up amongst academics, possibly fueled by the fact that there were ex-Pharma people now in academia who probably recognized some of these but couldn’t really talk much about them from their Pharma days. I know for Chris Lipinski, it was a breath of fresh air for him because he’s been increasingly exasperated at some of these full, high throughput screening hits coming out with real liabilities. So I think that’s probably why it hit such a nerve.

 

Barry Bunin

So, I want to talk a little bit about the CDD Vault, the software that we’ve developed.  Why did you decide to go with it for your collaborations there at Monash? What do you like about the technology based on your exposure to it thus far?

 

Jonathan Baell

Well, look, we did this before at WEHI.  So when we’re looking at a LIMS Laboratory Information Management System, we had a different one we hired, which was a competitor and it’s probably not fair to name what it is, so I will just specifically focus on what we liked about the CDD Vault. When I first came to Monash, I realized here was an academic environment with comp chemists, chemists making compounds, biologists getting assays, and it really needed a centralized system, a LIMS-type system, but one that could be afforded on an academic budget, and so we did the proper thing. We got a lot of demonstrations from various options in the area, and what I liked about CDD, and my colleagues liked, was the service, the friendly service and support, the patience in taking one through the initial demonstration, but also actually the fact that not a lot of patience was needed because it was so user-friendly, I just really liked the interface. I have to say I haven’t been disappointed in any way. Even in some of the earlier versions, a couple years ago perhaps – been more than a year ago, early functionalities we thought, gee that would be good to have – have since transpired to be the case and is implemented elegantly in the CDD Vault today. So, it is quite clear, CDD is a fairly active development team that responds to comments that people make. So, I would have to say the friendly interface, the usability, and we really like the web-based aspects. So we’ve got colleagues in University of Western Australia, they can log in and see what the latest data is, make a comment. We ended up duplicating targets, target compounds, and we’re comfortable that the security is tight. So, I would say we really like it, and the affordability in academic setting. I would have to say that probably sums it up.

 

Barry Bunin

To prepare for this call, I was looking at your website at some of the projects that you’ve mentioned like there was a mention of a PI3-kinase cancer project, T. brucei project, a malaria project, and so my question was both to learn a little bit about those interesting research projects within the context of which ones do benefit from the CDD Vault already today and which other collaborations maybe could benefit in the future, while also talking about the science.  I thought those topics would cover a good natural combination of science and technology.

 

Jonathan Baell

Yeah. Well if I were to log on to the CDD Vault right now, I would see what is growing every day with the projects. I’m not too sure what we’re up to, but it looked like there were 20 different projects last time I logged in. So, it really is getting widespread use. Interestingly, the PI3-kinase project that would be my colleague, Associate Professor Phil Thompson. I don’t believe they have uploaded the project yet into the CDD Vault. It’s actually a nice example of where sometimes these things take a bit of time in an academic environment. It’s not necessarily instantaneous where everyone loads up their data straight away. It can take a little bit of time just to change one’s mentality to a centralized way of working. The T. brucei one, of course, is my own and that was possibly the first project we started operating within the CDD Vault, so that’s now full of hundreds of compounds that are active against T. brucei and our colleagues who test in Griffith in Queensland and other states, upload to date the biological data from their end, and we’ve found that works very well. We did have a system where we had lots of different Excel sheets floating around and then the bilateral data would change or there’d be a data point that someone wasn’t happy with from a scientific perspective and then we’d have to make sure that the Excel master sheet was updated, et cetera, et cetera. That now doesn’t happen, so I think a few people are seeing that, and the advantages there, and so we’re increasingly getting these projects happening better in the CDD Vault.

The T. brucei, well I guess, as you probably know, it’s a neglected disease or it’s a parasite that causes a neglected disease, just sleeping sickness transmitted by the bite of the Tsetse fly. T-s-e-t-s-e, out of interest, if you look at the pronunciation on the Web, it gives both as Tsetse and Tsetse, and we’re not too sure which one’s correct. I still say Tsetse, it’s my English background. But this is a neglected disease and there’s a lot of interest amongst charity bodies trying to find cure for this neglected disease. Another one we’re about to work on some more, and that we’ve worked on a little bit on in the past, is Chagas Disease, again caused by Trypanosome. These are really actually nice projects for academic environments because students can talk about them openly. There are not IP issues associated with them because there’s no real market, so the funding bodies – charities such as DNDi which progress these compounds – don’t believe in patenting. The malaria, everyone knows about malaria. It’s not really a neglected disease. It’s one of these diseases which has benefited fantastically from philanthropy from the Bill and Melinda Gates Foundation. They really will be responsible, perhaps, for largely what we hope is curing a disease, within maybe a decade or so. There’s a lot of interest in vaccines, but we’re interested in the small molecule angle and we have a number of small molecules we discovered which are very potent against P. falciparum, the causative agent, and also has strong gametocytocidal activity which is of great interest at the moment for those working on malaria. We’re kind of fortunate at MIPS, we have an ADMET group called CDCO run by Professor Sue Charman, and they provide almost seamless access to some of the predictive AMDET and preliminary PK which you need to make the whole thing work. That’s those three projects, but there’s heaps of others.

 

Barry Bunin

So maybe for folks who aren’t so familiar with the impact of the top scientific discoveries in Australia, (obviously you won’t cover all of them, but I’m familiar with some of the work there because my background in combinatorial chemistry), like Mario Geysen’s pioneering work in Australia developing the mimotope pins for peptide libraries for finding epitopes. Through the neglected disease community I’m familiar with, you mentioned some of the work I’ve come across from Ron Quinn’s work with the Eskitis Institute at Griffith University and some of their collaborations. I believe there’s been a strong history of malaria research in Australia as well. So, I am just curious to hear what are some of the more interesting discoveries that happened from your experience inside that close knit community, and it can be for neglected disease or commercial drug discovery to just sort of showcase some of the more interesting things you’ve come across in your career there in Australia.

 

Jonathan Baell

Wow, well let’s see. That’s a tough question on the fly. And if I had 24 hours to think about it, I could probably talk for hours and hours. Straight off the top of my head, clearly you mentioned malaria. Malaria, for some reason (and it is hard to know the exact reasons why), Malaria research in Australia really is quite big and highly successful and I think it’s for a number of reasons actually. We’ve had key players in biology whether it’s Geoff McFadden, Leann Tilley, and other malaria biologists (http://www.ozemalar.org/). So, leading biologists in different area of malaria research are constantly making breakthroughs in terms of basically how the malaria parasite works. Alan Cowman, for example, has a long history of breakthrough science. He’s then attracted bright, young scientists who’ve then made careers themselves and made breakthrough discoveries. You know, the likes of Justin Boddey and Jake Baum, who have now just left for Imperial College. I think that’s one reason and the other reason is the centers such as CDCO with Sue Charman where they are really the PK engine for MMV (Medicines for Malaria Venture), and so that’s really the downstream stuff. They’ve directly been involved in compounds, specifically this Artemisinin-like peroxide compound which seems to be going all the way. And we’ve got the Australian Army Malaria Institute as well up north with Mike Edstein, and so they run animal models and much more. So I think the whole combination works pretty well.

Some other big breakthroughs are obviously cervical cancer vaccine which came out of Sydney and New South Wales leading to Gardasil from Ian Frazer’s collaborations. Going back a bit, I’d be remiss not to mention Relenza and with Peter Colman and Mark von Itzstein, Graeme Laver, who discovered the anti-flu compounds. Gee, what else? It’s numerous, numerous developments over the years. What is interesting in Australia is that we haven’t had the benefit really of a pharmaceutical med-chem research engine, and so medicinal chemistry has not been on the back foot exactly, but tends to have been lesser maybe in the spotlight than it might be in countries where there’s a big Pharma presence. But we’re certainly hoping to change that and I guess where I am now at MIPS, Monash Institute of Pharmaceutical Science, has become a bit of a med-chem powerhouse in Australia. So, we’re kind of hoping to tap into the aforementioned developments in Pharma looking at places like us to invest in and collaborate.

You mentioned another area of discovery I think?

 

Barry Bunin

I mentioned because I knew Mario Geysen’s work on epitope analysis…

 

Jonathan Baell

Yeah, of course, that’s right. Actually it’s interesting to some extent a lot of the younger chemists coming through here generally realize his place in this whole area. Even, in fact, going back to Merrifield with the solid phase peptide synthesis. A lot of people don’t necessarily realize what breakthrough discoveries were involved in those sorts of areas. Mimotopes is still going and are very popular. I don’t know if folks are familiar with these solid phase gadgets, onto which you load your peptides or your organics or many molecules, actually.

 

Barry Bunin

One of the things you mention about Artemisinin analogs caught my interest, so there’s been a lot of excitement about the availability of Artemisinin combination therapy for malaria. Over history, resistance has emerged to various therapies and so I’m just curious in terms of the pipeline for malaria, what are some of the interesting next things either needed or already coming down the pipeline from your perspective? What’s next that might catch folks’ eye, when we look back a decade from now?

 

Jonathan Baell

Malaria is really being attacked on all fronts, so as a medicinal chemist my primary interest is in kind of small molecule treatments and one notices some breakthrough compounds which are looking really good. For example, there’s a spiralindalone which came from screening a natural products library. I think it’s NITD, the Novartis Institute for Tropical Disease Research, and I think they only screened about 12,000 natural products. They got this natural product which is relatively simple and clearly did some excellent medchem to get this really potent compound, and it’s now actually progressing through the clinic and it’s actually looking really good. It’s one of these classical cases we have with microbes and parasites, antibiotics, and there’s a lot of interesting phenotypic screening first and you find the target later. That’s exactly how this compound was found. They did the screening first and then they kind of backtracked later to find the target, which I think from memory was involved in ATP Synthesis, but I’ll have to check that. You know, the same thing happened with bedaquiline, this anti-TB drug which was just approved late last year, when they found that it affects the proton pump associated with ATP Synthase. J&J, Johnson & Johnson, as far back as 1996, screened 70,000 compounds, came up with this compound which seemed to hit the model organism tuberculosis and to make a long story short, ended up with med-chem getting a compound, finding the target, and now it’s approved for multi-drug resistant TB.

So I think some of those are the exciting things coming through and, again, this peroxide-type compound which has really been developed on a lot of really clever mechanistic biology. You know, pursuing something which a lot of medicinal chemists, maybe with traditional Pharma outlook, just wouldn’t go near. A peroxide, whoa, who would progress a peroxide? Well, if you’ve got a certain hypothesis and research rationale behind it, then one should be open-minded to pursuing such things. So some of the later generations of that compound is progressing and looking really good, and of course, there’s a potential for vaccine. I don’t know a lot about the area of vaccines against malaria, but clearly that’s of great interest for kind of a semi-permanent cure, and so the Gates Foundation is putting a lot of research into that. And just last week I heard of what may have been some sort of breakthrough in terms of finding an appropriate binding epitope to generate a vaccine from. There is a whole area of genetics, to genetically modify mosquitoes to basically kill off the transmission that way. It even goes all the way to one of the most effective ways is simply providing better physical barriers, just simple sleeping nets. So, you’ve almost got every conceivable angle of attack on malaria and one hopes that one of those approaches, or a combination really, are going to come through with the goods, possibly within a decade.

 

Barry Bunin

Thanks for the broad thoughts on malaria. I want to come back to your own research and think about or share what you see in the foreseeable future and so the best case scenario, if your research goes well for your collaborations in the short-term, so say 6 to 12 months or very foreseeable future, what would be the interesting things you would like to see develop, and then thinking a little bit more broadly like 5 to 10 years, and it can be basic science or applied science. Share some of the things that you find interesting and motivating for you, and others may as well.

 

Jonathan Baell

I’m principally an academic so there’s a constant bubbling of different projects that are coming through student projects or grant funded projects. So for those, one of the main drivers is getting that POC. If it’s a med-chem focused quality publication, getting that J. Med. Chem. publication, for example. Better still if you collaborate with cutting-edge biology, you can get some really high impact factor papers. That is a definite driver for what I do, but being a medicinal chemist at heart, I am necessarily opportunistic. So anything that really looks like it could actually be associated also with something of therapeutic value, we then look at the progression path. How do we progress this? Can we, and if so, do we patent it? So in the area of cancer, for example, even malaria, one would have a patenting plan. So a couple of projects, at the moment in cancer, where we’re looking to that path, filing patents, and then the idea would be to part with that and progress that in a collaborative sense. That certainly worked really well at the Walter and Eliza Hall Institute basically for the last decade. I’ve only been MIPS for about a year. We had a project which started from a screening hit against BCL2, BCL XLs, some cancer targets, that went really well and ended up licensing with Abbott and Genentech and that progressed extremely well. It’s just starting to be published now. That’s the sort of model I see could really work here as well.

So the combination of quality papers, and I say quality papers – one of the things that does concern me worldwide relates to these PAINS. People are just finding compounds with a bit of activity and really publishing screening hits as though they are genuine optimisable candidates. And these things can be subversive and they can look real, so these publications are kind of getting accepted and unfortunately there’s a lot of noise out there, a lot of pollution, and this is one of the things we certainly strive to do here is not to publish something for the sake of publishing, but to publish it after making optimizations showing these are absolutely be real. So that would be our model. Publishing, patenting, if something looks really exciting, patenting first, then maybe publishing within 18 months of that patenting, and then seek to license. That is our sort of approach to get that outcome with the main focus areas being infectious diseases and cancer.

So we’re just starting a number of projects in antibiotic resistance research with colleagues here. The other big thing we want to do is to, on a Monash-wide (Monash is big, I think it’s got 50,000 students or something) scale, develop a right internal compound libraries. So, rather than just me –  at the end of this year we hope to have just from the last 12 months, 300 of our compounds stored in state of the art facilities in Queensland, called the Queensland Compound Library that’s all bar-coded, cherry picked, they’ve got an echo system which delivers narrowly and acoustically a stock sample for screening in assay ready format. Now we would like to, in fact, using with the help of the CDD Vault software to be honest, expand this initiative, not just to my compounds in the 300 over 12 months of my group, but every group at Monash. And actually develop our own sort of small screening HTS throughout discovery industry/facility internally. That’s probably one of the big picture stuff we really want to get happening. That’s probably going to take at least five years to get on a Monash-wide scale, possibly even ten. But that would be a bit of a vision on the grandest scale that I foresee happening.

 

Barry Bunin

Excellent. So, currently we’re at the formative stage of planning our next CDD user and community meeting for April 4th in 2014 to celebrate our 10-year anniversary. It’s memorable and a little funny as we were founded on April Fool’s Day so it’s easy to remember, four days later. So we have some confirmed speakers. So we have Chris Lipinski, we have Jerry Shipps who’s working with us with this Gates Foundation TBDA collaboration which involves seven big Pharmas working with academics and…

 

Jonathan Baell

Yeah.

 

Barry Bunin

…and various government labs as well. And then we have Bob Volkmann who is an ex-Pfizer scientist working at two biotechs using two different CDD Vaults, as well as Ruo Steensma from Orphagen Pharmaceuticals and other well known scientists. So those are some of the types of quality people that we have speaking. So, I guess my question is, as we’re planning this, are there any interesting people or interesting problems that would be good for focusing people’s attention where it’ll matter the most because we’re sort of setting up the agenda and the themes now. So, usually we have people give talks and I was even thinking maybe some people would just ask the community problems as another way of turning it on its head, but just wanted to sort of open up for ideas as we plan out our next gathering.

 

Jonathan Baell

Look, off the top of my head, I would say one of the big problems is one of the ones I almost just eluded to which is in academia the pressure to publish and the ability to publish, and again addressing these subversive compounds. I try to spread the message that a compound with a screening hit, a target-based screening hit with micromolar activity, if you triage those hit sets based on cell-based activity, you have likely to be picking for off-target compounds too. You often need to get to 500 nanomolar activity or lower target specific binding, in order to get meaningful cell based activity. I’m probably going into a bit fine print there, but that sort of general issue is something which I think the wider community still needs. There’s more and more people coming into screening, they’re overwhelming numbers, so the spread of knowledge of that sort of basic how-to stuff in drug discovery that the Pharma people would be well aware of will be useful.

Let’s see if I can broaden out a bit to bigger issues. I mean, the big things are really still private, public-private partnerships and how it’s working, and what the models are, is it successful, are there problems with gelling the private approach to the public approach in terms of the different needs or is it working really well? Is it context dependence, so does it depend on the project? Either it depends on the culture of the university or the actual Pharma partner. I can imagine there would be variables.

The other thing I’m kind of interested and I’d like to hear more about which, because it’s in Europe, so which we don’t mention it as much in Australia is the progress in this IMI initiative which you’ve probably heard about. I know they put in 500 million to…oh, I’d better warn you, someone’s cleaning my windows with an extremely high-powered hose. So I’ll block my ear.

 

Barry Bunin

…things spontaneously like this often get on the recording, it will come out in the text transcript which is funny. But yeah, the IMI you were mentioning, hearing what’s new from some of the European efforts, and there have just been big brain mapping research initiatives announced throughout the U.S. and in Europe as well.

 

Jonathan Baell

Yes, yeah, yeah, exactly. So I’ll be kind of curious to hear what’s happening there. I mean one thing which is of interest is this, and Ron Quinn could speak potentially about this too, he’s making this QCL, Queensland Compound Library. It’s really an Australian-wide initiative and where they’re going around universities and encouraging all universities to store their compounds, which is what I was talking about earlier where the Monash compounds would be stored up in the Queensland Compound Library, trying to get on an Australian-wide basis so it kind of got an Australia screening library that’s open access to everyone. The model there is that structures aren’t showing, biologists would access this publicly open library for all university libraries, if they get a hit they then talk to the biochemist at QCL about how to go forward. I don’t know if you’ve got room in your program, but that would be kind of an interesting talk because that could be relevant to other countries not just Australia. But, I would be happy to, if you wanted to leave that question with me, I’d be happy to give a small thought, Barry, and come up with some other ideas. I’m just trying to think of the issues in a community drug discovery setting.

 

Barry Bunin

I think those are good ideas and we’d like to have good diversity of types of scientists, types of institutes and geographies represented, so that gives me some food for thought already. I’m pretty much done with my main questions, I’m happy to give you the space for any last thoughts. Otherwise, I feel this is a very good spotlight interview.

 

Jonathan Baell

Oh good. All right, I’ve very much enjoyed it and I pretty much covered everything, this is a spontaneous process, so there will be things in your questions afterwards I think gee, why didn’t I mention that discovery or why didn’t I mention this. But I’m pretty happy with the spontaneity of the interview.

 

Barry Bunin

That’s what makes it fun. Well, thanks for your time Jon doing this across the Pacific Ocean. I’ll talk to you later.