Despite all the media attention on biologics and cell and gene therapies, Arnab Chatterjee, Ph.D., vice president of medicinal chemistry for Calibr at Scripps Research Institute, believes that small molecules still offer drug makers a faster route to new medicines for patients.
Chatterjee – who leads the non-profit group’s work with the Scripps Research Institute in development of small molecule drugs to treat a broad range of diseases – explains that in the early stages of development, once a small molecule compound shows therapeutic potential, “You are much closer to an actual product than you would be if you were to look in the arenas of biologics and cell therapies.”
Another advantage of small molecules, he adds, is the potential to repurpose existing drugs to treat different diseases. “We are spending a fair amount of time thinking about the general concept of drug repositioning; that is, finding molecules that may be very closely related to existing chemical structures used in humans, and trying to find new uses for them.”
Chatterjee suggests, “This idea that finding existing molecules and existing pharmacophores in interactions with potentially new target proteins is equally as important as it is for us to find new chemicals and pharmacophores.”
Calibr helps translate basic research discoveries at Scripps Research into commercial products. Calibr’s leaders describe their mission as the “first-of-its-kind, nonprofit translational research institute dedicated to creating the next generation of medicines” and they include biologics and cell therapies along with small molecules.
“We see drug discovery,” Chatterjee adds, “as being a key factor in providing equality to various underrepresented groups and underrepresented parts of the world that have not seen the profound effects of modern drug discovery in their day-to-day lives.”
Chatterjee joined Calibr six years ago after working as a medicinal chemist at the Genomics Institute of the Novartis Research Foundation. He received his Ph.D. in chemistry from the California Institute of Technology and his B.A. in chemistry and economics from Northwestern University.
WuXi AppTec Communications’ interview with Chatterjee is part of an exclusive series spotlighting the inside perspectives of thought leaders on topics shaping the future of new medicines.
WuXi: How diverse are small molecule drugs and how would you define small molecules?
Arnab Chatterjee: When I think about small molecules in drug discovery, I’m typically thinking about things that aren’t peptides or proteins or engineered cells. Rather I’m thinking about compounds, maybe somewhere around 1,500 daltons in terms of their molecular weight.
Typically, those are molecules that can either be synthesized entirely from very simple organic building blocks or are compounds that can be derived from natural sources, such as carbohydrates, amino acids, nucleic acids and natural products that occur from various other species.
WuXi: How has small molecule drug discovery changed?
Arnab Chatterjee: In many ways now, small molecule drug discovery is very much driven by understanding not only the biochemical interactions of molecules with their potential target proteins, but also by better characterizing small molecules in the way that they interact with cells and how cells interact with other cells.
For example, in the area of immuno-oncology you’re not only looking at the particular biochemical targets, but you’re also looking at different cell-based systems and eventually in vivo systems. Cell-based systems can better understand the variety of targets that small molecules may be affecting versus a monoclonal antibody or a peptide or molecules of larger molecular weight, which typically have much more specific interactions with target proteins inside of cells and inside of various organisms.
WuXi: How are specific small molecule compounds found?
Arnab Chatterjee: I think people are still using screening methodologies to make single compound libraries; for example, what was done 20 years ago in the combinatorial chemistry area
But you now have things that are called more dynamic libraries, which means you use more sophisticated screening methodology to find the compounds, such as DNA-encoded libraries or even more complex computational tools, such as structure-based drug design. But you’re looking at large numbers of compounds and interactions that may exist between a small molecule and target protein.
I think it’s certainly expanded. I think the use of chemical tools, to use high throughput screening or even low and medium throughput screening still does center around two basic elements. One is investigating novel chemicals space – molecules or bonds or interactions between atoms in a covalent manner in structures that simply have not ever been made or tested – is still a significant effort within the biotech, pharmaceutical and academic arenas.
The other element is that we are spending a fair amount of time thinking about the general concept of drug repositioning. That is, finding molecules that may be very closely related to existing chemical structures used in humans, and trying to find new uses for them by finding very subtle structure activity relationships that may allow one to use a very similar molecule for a completely different disease.
WuXi: Do small molecule drugs have advantages over biologics and other treatment modalities, such as cell and gene therapies?
Arnab Chatterjee: I would argue that the biggest advantage of small molecule drugs is to be able to produce those drugs in both small quantities and eventually in large quantities that are readily accessible by people in various different resource environments such as low resource countries, and medium and high resource countries like the US and China.
I would also argue that the single most exciting part about small molecule drug discovery is that you are much closer to an actual product than you would be if you were to look in the arenas of biologics and cell therapies.
The bottom line there is you are generating drug products that you can test in animals and then into humans at a much faster rate than you can with those other modalities, where scaling up the therapeutic even to perform toxicology studies is a significant challenge in terms of resources required.
The real advantage that we’ve tried to employ within Calibr – and now part of Calibr Scripps Research – is the concept that we can more quickly test hypotheses in settings where we may need a large amount of drug substance. That is a bigger challenge for those other modalities.
WuXi: Are there certain diseases where small molecule drugs would be preferable. In the future, will small molecules be able to do everything biologics can do?
Arnab Chatterjee: I think that target specificity is going to be a challenge (for small molecules) because you simply don’t have enough atoms and enough interactions. The specific interaction with the target proteins, both in terms of potency and selectivity, is something that will be challenging for small molecules – just based on first principles of molecular interactions.
On the other hand, for cellular (targets) – what we already know from drug discovery over the past 150 years or so – the pharmacology that you can get out of a small molecule is as good, or perhaps even more robust, than biologics and other types of modalities.
Now that being said there are specific disease areas such as oncology where the effects of biologics and cell therapies are very profound and there may be specific diseases like that where a small molecule may not be able to reach that level of activity in pharmacology.
However, in other disease areas such as infectious diseases, autoimmune diseases, and probably cardiovascular diseases, small molecules can have multiple interactions with multiple proteins, which drive pharmacology. In that manner there are a significant number of disease areas where a small molecule can go toe to toe in terms of potency.
And then when one considers factors such as the cost of the eventual drug product to the patient, there may be more drug required for a small molecule, but the cost would balance out or, in some cases, be advantageous to biologics and cell therapies.
WuXi: How are small molecules being used to improve our understanding of biology?
Arnab Chatterjee: That’s a great question. In actuality, that is at the very crux of the techniques that are being developed within the academic community, which I think have profound impacts on understanding the multiplicity of interactions that small molecules have with potential target proteins inside of a cell, and inside of organisms and humans. The ability to have small molecules of various different types of chemical structures and to understand their potential new interactions is something that is very, very important.
So that’s why – to my earlier answer – I suggested this idea that finding existing molecules and existing pharmacophores in interactions with potentially new target proteins is equally as important as it is for us to find new chemicals and pharmacophores.
WuXi: How are small molecules being used in combination with biologics? For example, how are small molecules being used with immunotherapies?
Arnab Chatterjee: People are realizing that you can affect particular types of interactions between immune cells and cancer cells, even potentially between an immune cell and an infected cell, be it bacteria or virally infected cell.
All those interactions where a biologic may be able to do somethings, a small molecule can be combined. One great example, one that has been used for a very long time has been coupling biological vaccines, either cell-based vaccines or antibody-based vaccines, with small molecule adjuvants where you are activating an innate immune system to be able to boost the response of the vaccine, which in many cases may be limited in terms of its intrinsic potency.
So, I would say that while this is happening very recently in the immuno-oncology space, in fact, immune activation in immune-infective models has been done for a long time.
WuXi: What kinds of research and drug development are you focusing on at Calibr?
Arnab Chatterjee: We have taken a very agnostic view to drug discovery in terms of unmet medical need. While I would say we have a great deal of interest, and have active programs, in small molecules, biologics and cell therapies, in the oncology space, we also have spent a lot of our time thinking about infectious diseases and diseases that have significant unmet need in under resourced environments.
We have done a lot of drug discovery in the last year-and-a-half and we now have two things in development that are centered around repurposing existing drugs for infectious diseases. In the case of tuberculosis and cryptosporidium infections, they are drugs that have been used in other indications and we are now applying them to novel indications where there is a significant unmet need in under resourced environments.
That, really for us, centers around the general concept that we see drug discovery – we see new medicines for unmet needs –as being a key factor in providing equality to various underrepresented groups and underrepresented parts of the world that have not seen the profound effects of modern drug discovery in their day-to-day lives. We see a value in doing both of those things in parallel with a similar level of veracity and enthusiasm for getting new therapies into patients.
We also have one small molecule therapeutic in clinical trials in the regenerative medicine space. It’s a molecule we now have in Phase 1. The molecule was invented and created within Calibr. It’s a small molecule that regenerates mesenchymal stem cells in the knee to produce cartilage to potentially correct systems and pharmacologies related around osteoarthritis.
We have several other small molecule programs that are headed towards the clinic in various different disease areas. But as I mentioned regenerative medicine, immune-oncology, infectious disease are all important disease areas for us where we see significant unmet need.
WuXi: How are you translating this research into commercial development?
Arnab Chatterjee: We see Calibr and our strategic relationship with Scripps Research as a means of taking really interesting potential new therapeutics of various different types into early clinical development.
Our osteoarthritis medicine is really an example of what we believe is the first of its kind of drug to be completely developed in a non-profit environment and moved into clinical trials exclusively through a non-profit working with other groups, but no commercial partners for the therapeutic. We certainly would entertain commercial partners going forward towards (hopefully) registration.
So, we see that possibility, and this includes everything including IND enabling studies, GMP manufacturing of the final drug product, and then actually beginning trials at various different sites with a clinical path forward into a proof of concept study. We see great value in being able to do it within an environment like Calibr where people are still very closely associated with the program – from those who started the program – versus licensing and sending compounds and programs outside of the walls of Scripps Research. We see great value in doing that and then finding commercial partners as we get further along in the process.
That being said, we have also done a few programs, particularly in non-small molecule drug discovery, where we have partnered with various groups pre-clinically. One example is our work around CAR T cells and engineered cells for various indications in oncology where we partnered with the large pharmaceutical company, Abbvie. We partnered with Abbvie a little bit earlier in the process, but much further along where we have things that we think are the actual candidates that we could take into a clinical trial in humans.
We see a great opportunity to not only work with various different academic collaborators throughout the world, but more specifically working very intimately with various investigators at Scripps Research both in La Jolla, CA, and Florida. We can work very closely with discoveries made in various principle investigators’ labs where they may have a great deal of interest in being part of the drug discovery process versus out licensing and creating start-up companies, and other means that have been more traditional.
WuXi: How far in the clinical development process do you go?
Arnab Chatterjee: We have gone into Phase 1 and Phase 2 studies. I don’t see a stage right now where we would do a pivotal registration trial. But we do see value in being able to take things into early and mid-stage clinical development. At that point we have a better idea of what we’re trying to establish and whether we are seeing clinical benefit with those compounds.
WuXi: You are in a good position to see what interests big pharma and big biotech companies. What’s driving them? What are they focusing on?
Arnab Chatterjee: There’s a great deal of plasticity in the answer to that only because it changes a lot. We have seen specific disease areas come greatly into favor and out of favor just in the last six years I’ve been at Calibr.
I would say in areas such as neuroscience and infectious diseases, most recently, there has been a significant downturn in terms of the interest for taking significant risk in preclinical drug discovery. Though I would say that one of the real valuable parts of our alliance and relationship with folks at Scripps Research is that there is still very interesting basic research being done in these areas.
My general feeling is that having a very broad approach to dealing with disease and a very broad approach to thinking of the interactions of various things like the immune system – not only in the context of cancer but also in the context of autoimmune diseases, infectious diseases, cardiovascular disease, and metabolic disease – is definitely something we would want to continue pushing and generating novel and interesting assets. At some point those things, while they fall out of favor for some period of time, do become in vogue again and at that point it’s important to have things that we can present to patients.
WuXi: How will the drug modality mix – our toolbox for disease treatment – evolve over the next five-to-10 years?
Arnab Chatterjee: This whole concept of doing small scale proof of concept studies in rodents, particularly, is something that biologics, cell therapies, non-small molecule modalities have a leg up on.
The ability to generate interesting in vivo proof of concept using those modalities is something that can happen quite quickly especially with modern tools of recombinant genetics and all of the things that are available with the tools of cellular engineering. That being said, there is a significant challenge in being able to take those translations to something that can actually be presented to patients.
With small molecules there may be work required at the early stages of drug discovery – that is, to get a molecule that has good enough properties to be able to show activity in a rodent disease model, but then from there, there may be less challenges to get to a drug product that is presented to humans.
At the crux of this is the concept of how quickly, in the small molecule drug discovery space, can we use a variety of different screening tools to generate novel chemistry and demonstrate proof of concept as quickly as possible in animals. That is really going to be – at the end of the day – the way small molecules will be able to close that critical gap that has emerged in the last 20 years where there have been more and more biologics, cell therapies and gene therapies presented to patients with disease.