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Targeting “Undruggable” Proteins by Selectively Controlling mRNA Translation

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Many human diseases are driven by the dysfunction or dysregulation of proteins. However, up to 80% of proteins do not possess binding sites suitable for direct binding of small molecule drugs, making them “undruggable”. To overcome this problem, Anima Biotech has developed their Translation Control Therapeutics platform to identify drugs with the ability to interfere with the production of these “undruggable” proteins, by selectively inhibiting the translation of mRNA.

Technology Networks spoke with Yochi Slonim, cofounder and CEO of Anima Biotech to learn about the company’s novel drug discovery approach. Slonim also discusses Anima Biotech’s internal pipeline program that spans multiple therapeutic areas with high unmet need – and “difficult” drug targets.

Laura Lansdowne (LL): For readers that may not be familiar with Anima Biotech, could you tell us a little about the company history and mission?

Yochi Slonim (YS):
Anima Biotech is advancing Translation Control Therapeutics, the first discovery platform for small molecule drugs that selectively control mRNA translation. This is a new strategy against proteins that have been deemed hard targets or “undruggable”, because they lack pockets on their surfaces where small molecules drugs can bind. Instead of trying to go after these proteins in a direct manner, Anima is taking a novel approach by discovering drugs that control the translation of the mRNA into proteins by ribosomes. Our proprietary technology uses fluorescently labeled tRNAs that when transfected into the cells, the ribosomes generate light pulses when they assemble the protein. A small molecule library is screened to identify “active hits,” or compounds that decrease or increase the light, as they affect the translation of the protein. We then pass these hits through proprietary analyses to check their specificity and to understand their mechanism of action. Because of the selectivity of the biology that controls translation inside cells, small molecule drugs that affect translation can even distinguish between the same protein in different tissues, different cells, pathways or even between normal and mutated mRNAs.

Anima’s platform initially came out of the University of Pennsylvania and the science is backed by 15 scientific publications, 17 academic collaborations and our six drugs discovery programs across therapeutic areas. In July 2018, Anima Biotech and Eli Lilly & Co. partnered together in a $1B collaboration for the discovery and development of translation inhibitors against several target proteins in the neuroscience space.

Could you touch on some of the traditional drug discovery methods and the limitations and challenges related to these?

Protein dysfunction and dysregulation are the major drivers of the majority of human diseases. In most diseases, you see a certain protein that goes out of control. Either there is too much of the protein (many cancers are associated with such “over-expression” of proteins), too little of it (common in neuroscience), or it may be mutated (as in the case in many genetic diseases, such as Huntington’s disease).

Historically, drug development in the pharmaceutical industry has been focused on developing small molecule drugs that are designed to directly bind proteins that contain specific structures or “binding pockets.” Unfortunately, up to 80% of proteins do not have suitable binding sites, or pockets, able to be targeted via the direct binding of small molecules to influence their biological activity. In fact, the totality of currently approved drugs interacts with only 2% of human proteins, highlighting the inability of traditional drug discovery to target proteins effectively. Therefore, despite the investment of tremendous time and resources across the industry, many proteins involved in diseases have not been successfully targeted and remain known as “hard targets” or even declared as “undruggable.” A good example is a protein called cMyc, which is over-expressed in most types of cancers. It has been a target for over 30 years with no success in finding drugs that can bind to in because its chemical structure is very challenging. With our platform we don’t really care about the chemistry of the protein itself since we have a different strategy – we identify drugs that interfere with its production to begin with. In this way, we succeeded in identifying small molecules that selectively inhibit the translation of the mRNA of cMyc, effective across a wide range of tumors that are cMyc producing.

Other approaches have attempted to target the mRNA of undruggable proteins. One such technology is known as RNA interference (RNAi). This requires injection of the RNAi-based drug to the specific disease site in the body, as these drugs are not small molecules and they cannot be administered orally. However, the actual delivery of the siRNA molecule into the target site remains a major challenge as these drugs, like mRNAs, degrade very quickly in the body.

More recently, new approaches have been developed to directly target mRNA with small molecules. These new modalities are still in very early discovery stages and are yet to be deemed effective. In addition, it is not currently clear how specifically these methods are able to target diseased tissue without causing major toxicities. The main reason is that unlike RNAi that is injected into a target tissue, small molecules can reach every organ in the body. If the molecule is targeting the mRNA of a protein which is expressed in many tissues, major adverse effects can arise. It is also not yet clear how targeting mRNA can achieve the required clinical effect since the precise biology and mechanisms involved when interfering with mRNA through small molecules is not well understood. Finally, for those diseases where the problem is “under-expression” or lack of protein, there is no way to increase a protein's production by “knocking down” its existing mRNA. This is essentially a one-way strategy that can only hope to decrease certain proteins.

LL: How does Anima Biotech’s novel drug discovery approach exploit
mRNA translation and protein synthesis? What are the benefits to using this approach?

Anima is also working to target mRNA biology with small molecules, but in contrast to the approaches mentioned above, we are not targeting the mRNA molecule itself. Instead, we identify drugs that interact with the mechanisms that cells employ to regulate and control translation. Because protein translation is a highly selective process, small molecules that affect translation can be highly selective towards tissues, cells and pathways meaning they are expected to have a better safety profile. Additionally, the mechanisms inside cells enable the decrease and increase of the production of any protein – cells do this constantly. So, by targeting the proteins that regulate translation, one can have a two-way strategy and identify drugs that can either decrease or increase the production of almost any given protein in a specific manner.

This strategy is applicable to a very wide range of challenging and undruggable targets and gives new hope that we can treat many diseases that today have no effective treatments. What is important to note is the fact that although this represents a breakthrough as a therapeutic approach and in a new target space, the development of these small molecules still follows the traditional pharmaceutical development path. That means that from the minute we have identified the molecule and its mechanism of action, we can easily partner with pharmaceutical companies to continue its development. It is an approach that is highly innovative at the onset, but completely compatible with established processes downstream.     

A major feature of our platform is its proprietary ability to
rapidly elucidate the mechanism of action of our drug candidates and to understand exactly how these compounds work in addition to how they affect the translation process. This means that our technology does not only discover drugs, but it also discovers novel targets that have not previously been exploited in drug development.

LL: What drug candidates are currently in your R&D pipeline and what indications are these being developed to treat?

Our discovery platform has repeatedly identified compounds in multiple therapeutic areas, including fibrosis (tissue selective Collagen I translation inhibitors), oncology (cMYC translation inhibitors), viral infections (Respiratory syncytial virus (RSV) translation inhibitors), neuroscience (our collaboration with Lilly on undisclosed targets) and rare genetic diseases such as Huntington’s disease. Our most advanced program in pulmonary fibrosis is set to enter clinical studies within 12–18 months and our cMyc program in oncology is expected to follow it shortly after. All our programs have successfully identified drug candidates that control extremely difficult-to-target proteins.

For instance, in our lung fibrosis program we inhibit the translation of Collagen I, a structural protein that accumulates in patients’ lungs. Collagen cannot be targeted directly since it has almost no chemistry to go after and besides, it is the most abundant protein in the body, so its mRNA is literally “all over the place”. However, our drugs inhibit the accumulation of Collagen I in a tissue selective manner, something that has never been seen before with small molecules. They exclusively affect the production and accumulation of collagen in the lungs, without influencing its production in other tissues such as in the liver, skin or bones. The magic is not in the compounds, they are just small molecules which means that they really go everywhere and reach the cells in those other tissues. Rather, it comes from the fact that the regulation of the translation of collagen is done differently in different tissues therefore by going after those mechanisms we can identify drugs that work only is a specific tissue type. You cannot achieve such an effect by directly targeting the mRNA of collagen.

In our oncology program, we inhibit the translation of cMyc, a very famous oncogene that has been unsuccessfully targeted by the pharmaceutical and scientific community for over 30 years. In this program, we again see the major advantage of our approach when it comes to selectivity. Our small molecule candidates are able to distinguish between cancerous and healthy cells and to affect only the diseased cells. This comes from the fact that cancer cells modify the translation process in a unique way that we can go after.

In our anti-viral program, we discovered small molecules that inhibit the translation of the RSV, the leading cause of lower respiratory tract infection in infants and young children. Again, here we are not targeting the virus itself but rather the translation process which the virus highjacks for its replication. This mechanism is known to be used by many different viruses so our molecules can potentially be effective against other viral infections. This pan-antiviral drug can be thought of as a sort of “viral antibiotic.”

Lastly, we have programs in an area known as “repeat-associated diseases”. This is a group of dozens of genetic diseases in which a mutated sequence is repeated over and over again in the gene of a specific protein. When the ribosomes attempt to translate the mutated mRNA, they end up producing mutated and harmful proteins that in some cases “get stuck” altogether resulting in many other side effects. In the case of Huntington’s disease, with our technology, we discovered molecules that can inhibit the production of the mutated Huntingtin protein without affecting the “wild-type” or normal copy of the protein. We are currently repeating this strategy against additional repeat associated diseases for a novel strategy in that space.

Overall and in summary, Translation Control Therapeutics is a new approach driven by new technology that enables us to control the translation of mRNAs. Our platform has been validated across many therapeutic areas and programs as well as by our collaboration with Lilly. It is a two-way strategy that can either decrease or increase proteins. It can selectively control mutated proteins without affecting the normal version of the protein. Translation-controlling drugs come with great selectivity since they target the highly selective mechanisms that cells themselves use to regulate translation. Finally, at the back end of the discovery process, we are gaining access for the first time to the novel targets that control translation, a rich, untapped source for new drugs.

Yochi Slonim was speaking with Laura Elizabeth Lansdowne, Senior Science Writer for Technology Networks.