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Targeted protein degradation and a new era of proteome therapy
Our monthly thematic long-reads are free. Over the next two weeks, we will release ~1,500 word deep-dives for each company covered in our shortlist for subscribers only, along with research notes & due diligence on other biotechs. We also provide a rapid turnaround due diligence service for those interested.
This month, we cover Targeted Protein Degradation (TPD) & PROTAC (Proteolysis Targeting Chimeras), a promising therapeutic modality that we believe will revolutionize small molecule drug design. Paired with a rapidly growing scientific understanding of the human proteome and its role in disease, TPD could do for protein-targeting drugs what microprocessors did for the PC — accelerating a new generation of capabilities and use cases to transform the relationship between humans and pharmaceutical treatment.
This essay begins with 1. what TPD is and 2. TPD in 2021 & beyond, before a 3. deep scientific review, concluding with 4. the Parallax View and 5. our picks.
1. What is Targeted Protein Degradation? 😎
In fifty words (TL;DR)
The regulation of protein concentration and quality is critical to life. Cells use two major pathways to degrade proteins: ubiquitin-proteasome system (UPS) and lysosomal proteolysis. Targeted protein degradation is the process of targeting disease-associated proteins for destruction. Existing technologies focus on using drugs to hijack the UPS to degrade a protein of interest (POI).
In three-hundred words (Science 101)
The regulation of protein levels is a critical process required for healthy equilibrium in all your body’s cells. Altered expression or activity of single proteins is linked to numerous diseases of varying severities. Historically, small molecule inhibitors (SMIs) have been employed as a tried-and-true method for treating disease at the proteome, succeeding due to their oral formulations, high bioavailability, and manufacturing/distribution scalability which has enabled widespread adoption of life-saving treatment in both developed and developing markets. Read more about SMIs in this footnote.
Since the majority of disease-causing protein targets do not have accessible active sites or allosteric binding sites, a majority of disease-causing proteins have long been considered undruggable. While monoclonal antibodies (mABs) have emerged as an alternative therapeutic modality, they face challenges in their often artisanal manufacturing scalability, complex distribution, cost, inconvenient administration, tolerability, and ability to target intracellular proteins. Furthermore, biologics still largely work via a lock-and-key mechanism, meaning that even with the additional power of biologics, small molecules and antibody-based drugs together target only ~20% of the human proteome.
To overcome this limitation, researchers are developing a new a technology that is scalable and has the potential to modulate a broad range of targets. While still in its infancy, Targeted Protein Degradation (TPD) has entered the clinic and could soon become a proven method to “drug the undruggable”. Since TPD utilizes a unique mechanism of action it will likely have a unique set of advantages and a disadvantages. TPD promises benefits that SMIs and biologics cannot, because instead of neutralizing disease causing proteins, they destroy them — potentially avoiding toxicity caused by high doses needed to inhibit a majority of disease-causing proteins or disease resistance that occurs when proteins mutate and evade inhibition.
A Brief History of TPD
TPD as a theoretical approach is technically not a new idea. Some 20 years ago, Proteinix was founded and received a NIH small business innovation research (SBIR) grant to develop a TPD drug for the treatment of HIV. In patent US6306663B1, filed by Proteinix in 1999 (not to be confused with Craig Crews’ Proteolix founded in 2003), the inventors describe a method that, instead of messing about with locks and keys like SMIs or mAbs, enlist the body’s own protein recycling system, the ubiquitin-proteasome system (UPS), to dismantle specific disease-causing proteins by providing additional toolkits to the machinery that naturally degrades unwanted proteins so that they can recognize disease-causing proteins and trigger their disassembly.
Though the vision Proteinix put forth was prescient, the development of this technology languished without an established understanding of UBS biochemistry. Now, over a decade later, seminal research in TPD has been published, rapidly transforming the field from a lab curiosity to a potentially groundbreaking medical technology. Drugs using TPD tech have already been FDA approved, though it was not known then that they used UPS.
Consider the fascinating case of Lenalidomide – the third highest grossing prescription drug in the world and a major commercial success for Celgene under the brand name Revlimid, generating $12.5 billion in 2020 sales. It is a monofunctional degrader of IKZF1 and IKZF3, and was approved in 2005 for the revolutionary treatment of multiple melanoma (MM). However, its mechanism was unraveled only in 2014, when two independent groups of researchers contemporaneously published its activation of the ubiquitination pathway in Science, establishing it as the first approved protein degrader. Lenalidomide is a part of a class of drugs known as immunomodulatory imide drugs (IMiD), which bind E3 ligase Cereblon (CRBN) to initiate ubiquitination and protein degradation. Since the approval of Lenalidomide, several independent studies have shown that therapy in newly diagnosed transplant ineligible patients yields a ~20 month increase in progression free survival compared to previous standard of care.
Mechanism of Action of PROTAC (Science 201)
Difficult to treat cancers and diseases are often caused by faulty or even harmful proteins. Depending on the condition these proteins can either be structural proteins or enzymes. Today, some of these illnesses can be treated using different types of medicines, but in most cases, it comes with the risk of developing a higher tolerance towards the drug, which means that a higher dose of the drug is needed for it to work properly. This increases the risk of unwanted side effects. Luckily, a new type of molecule is showing promising results in terms of treating both cancer and “untreatable” diseases such as Alzheimer’s. Besides the ability to treat diseases caused by structural proteins, which is quite unique, they can also be used in much lower doses than traditional drugs, which lowers the risk of negative side effects significantly. These molecules are called PROTAC (Proteolysis Targeting Chimera).
PROTAC is an approach to TPD
PROTAC are heterobifunctional degraders (more on this later)
Arvinas ($ARVN) trademarked the term, so many other companies have their own similar abbreviations to describe the same thing
Yale University licensed the PROTAC technology to Arvinas, founded by Yale Professor Craig Crews, in 2013
PROTACs facilitate the removal of unwanted proteins through a process called selective intracellular proteolysis, or in other words, breaking down specific proteins inside the cell by recruiting the help of proteasomes already found in the cell. Proteasomes are often referred to as the waste disposal system of the cell, as they help degrade unwanted proteins and recycle their amino acids. But how do the PROTACs let the proteasomes know which proteins to break down?
PROTACs are small molecules that consists of three parts – two domains and a linker that connects the two domains. One domain can bind selectively to a specific protein. The protein that this domain can bind to is called the target protein and varies across different PROTACs. While the domain is bound to the target protein, the other domain will be able to bind to a special kind of enzyme found in our cells called an E3 ubiquitin ligase. When this happens, the E3 ubiquitin ligase recruits an E2 ubiquitin-conjugating enzyme that marks the protein – just like when a forest worker makes his way through a forest and marks the trees that need to be cut down later. In the case of PROTACs, the marking is called ubiquitination (the ‘kiss of death’ for a protein), since the E3 ubiquitin ligase places a small protein called ubiquitin on the protein that needs to be removed. Along comes the proteasome, and when it happens upon a protein that has been marked with ubiquitin it starts to break it down. The amino acids that the protein is made of are recycled as building blocks for new proteins within the cell. The fact that the target protein is broken down and not just inhibited means that a single PROTAC molecule can degrade multiple target proteins, lowering the dose required and potentially extending the therapeutic effect significantly, providing a benefit to both long-term efficacy and tolerability.
2. TPDs in 2021 and its Outlook
Types of TPD Today
Two major platforms of TPD drugs exist, and while monofunctional and heterobifunctional degraders look very different, their mechanisms of action are similar:
Monofunctional degraders (e.g lenalidomide) are single molecules that bind the desired E3 ligase and then the protein for targeted degradation, acting as a “molecular glue” that connects the two molecules as one cohesive complex. The proteins that bind the E3 ligase-monofunctional degrader complex are commonly referred to as neosubstrates.
Heterobifunctional degraders use two molecules which are tailored to bind to each of the protein of interest or an E3 ubiquitin ligase. They are covalently linked by a semi-flexible chain designed for optimal proximity of the ligase to the protein for degradation
Despite lenalidomide’s early success as a monofunctional degrader, heterobifunctional degraders such as PROTAC have emerged as the more promising approach to TPD, largely because monofunctional degraders lack a set of well-articulated design principles. As a result, the discovery of monofunctional degraders has largely been serendipitous and novel design has largely stalled. Those monofunctional degraders that are under clinical investigation are primarily derivatives of thalidomide (similar to lenalidomide) and target E3 ligase CRBN, translating to minimal novelty and lackluster realization of TPD’s potential.
At the time of writing, the total market cap of our shortlisted TPD picks is at $11B (roughly the same as Levi Strauss & Co). We believe this could grow tremendously in the next few years if efficacy is reported across the board. Currently, ~$5 billion has been invested by both private and public investors and 90+ agreements were inked between 2014 and 2019. Partnership activity in TPD has increased at a CAGR of close to 40%.For future growth, some institutions predict that the CAGR from 2020 to 2027 will be over 10%.
The commercial TPD landscape has become significantly more crowded in the last 2 years, with dozens of TPD-focused companies, which we view as a promising sign for the future of proteome treatment. Given the disruptive potential of this technology and a gigantic addressable market across diseases in nearly every indication category, the value proposition is enticing despite the early risk presented by an unvalidated clinical modality. Big pharma seems to agree — in 2019, BMS shelled out $74 billion for Celgene, which had two monofuctional degraders, Revlimid and Imnovid, as its main assets. Since success in the clinic for any single company pursuing a non-thalidomide derived degrader system may be interpreted as proof of concept for TPD in humans as a modality, early trials could deliver good news for most companies in the space. Unfortunately, the opposite is also likely true in biotech. The cumulative results of the clinical trials currently underway or commencing in the second half of 2021 will be fundamental for validating and shaping the future of this technology.
TPD Drugs Under Clinical Investigation
Other TPD-related players to keep an eye on: Vividion (acquired by Bayer in August), Scorpion, PAQ (CN), Lycia, Amphista (EU), BiotheryX, Captor, Cedilla, Hinova (CN), Monte Rosa ($GLUE), Palleon, Halda (Dr. Craig Crews’ stealthy third company, discussed later), Orum (KR), Progenra, PolyProx, UPPthera (KR), Plexium, Frontier, Seed (under $BYSI), Roivant, Ranok (CN), Mission (UK), Cullgen (CN), Foghorn ($FHTX), Dialectics, FIMECS (JP), Pin, Ubix (KR), Lycia, Orionis (EU), Trilo, Casma, Autotac, Ribon, Kintor (HK.9939), Aurigene (IN), Stablix.
Future Outlook of TPD
There are several hundred (~600) putative E3 ligases that are underexplored or unexplored that could greatly expand the applicability of this technology. In an ideal case there are numerous E3 ligases that have highly localized expression specific to disease tissue, and ligands that are in the accessible chemical space. In this case it is easy to imagine a world where bountiful TPD drugs could be developed to selectively degrade ubiquitously expressed proteins in a highly context-specific manner, avoiding off-target effects. In such a scenario, ligands for the protein target would not need to be as selective as current SMIs. Even though TPD drugs would still interact with off-target proteins in healthy areas of the body, the lack of corresponding E3 ligase would prohibit degradation, limiting side effects. Additionally, it may be possible to develop protein-binding motifs specific to mis-folded or mutated forms of a protein, allowing for highly precise molecular reductions even when a ubiquitous E3 ligase is employed.
Companies in the space are building research tools that deliver value beyond their current pipeline candidates, funding basic research to elucidate TPD’s underlying mechanisms and best practices for therapy design. Proprietary commercial discovery platforms seek to identify new proteins of interest, E3 ligases, and their relative localization in the body. Many of these companies use DNA-encoded libraries (DEL) and statistical models to identify the optimal ligand for a therapeutic TPD system.
Looking forward, new techniques addressing the potential shortcomings of current TPD are being developed as “TPD 2.0”. One current shortcoming is that E3 ligases are only found within cells, therefore UPS based techniques are not able to degrade disease-causing proteins in the extracellular space. Lycia is developing Lysosome Targeting Chimeras (LYTAC), which leverages the lysosomal trafficking system to target extracellular proteins. Another challenge with current TPD is that many drugs employ E3 ligases that are expressed throughout the body, creating the risk of off-target effects. To solve this issue, Orum Therapeutics (private Korean-US) is developing Antibody Degrader Conjugates (AnDCs), where a protein degrader is conjugated to an antibody to improve localization. Further, there are numerous protein aggregates linked to disease that are not degraded by the proteasome but rather by the autophagosome. In these cases, molecules that hijack the intracellular autophagy degradation pathway are being explored, called Autophagy-Targeting Chimeras (AUTAC). This technology cannot degrade proteins inside the nucleus, but it should be capable of degrading larger objects or aggregates in the cell, an approach that could prove superior for eliminating insoluble protein aggregates in systems like the brain. Finally, there are Autophagosome-Tethering Compounds (ATTEC) in early novel development by PAQ Therapeutics. Both AUTAC and ATTEC are Macroautophagy Degradation Targeting Chimeras (MADTAC).
In short, keep an eye out for LYTAC, AnDC, MADTAC (i.e. AUTAC & ATTEC), in addition to PROTAC 😉
3. Science 301 Review: Notes & Questions
Note: This part is a more advanced scientific review for our nerdier readers
👍 Advantages of TPD
1. Can drug the undruggable
a) Since we do not need super high affinity binders we can go after proteins that do not have well defined grooves or pockets, which are features that make a target considered druggable under SMI or mAb “lock and key” paradigms
b) Can go after targets like transmembrane proteins, membrane associated proteins, scaffold proteins, or transcription proteins
2. Catalytic mechanism of action means that a sub-stoichiometric amount may be effective, allowing for much lower dosage, with two major advantages:
a) This mitigates loss of function due to the low bioavailability caused by its relatively larger molecular weight (one of TPD’s violations of Lipinski’s rule of five)
b) Avoidance of dose limiting toxicity, especially if the system can be designed with catalytic localization to target proteins or ligases specific to diseased tissue
3. Scalable manufacturing – TPDs are organic molecules manufactured by synthetic chemists in a flask, avoiding the complex, supply-chain limited, and temperamental manufacturing process of biologics made by cells grown in 1,000 L+ fermenters
4. TPD drugs are orally bioavailable and do not require injection – the marketing advantage of needle avoidance should not be underestimated and reduces distribution and administration cost substantially
5. Tunable – theoretically would allow modulation of protein concentrations to achieve desired titers, rather than a binary switch on expression, allowing for treatment of protein diseases where complete knockdown of a target poses a risk
6. Target protein ligands and E3 ligase motifs can be mixed and matched to achieve desired properties, hence the value of proprietary target and ligase binder libraries
7. Less invasive and more flexible than gene editing approaches like RNAi
a) No off target splicing since it is not editing the genome
b) Change in protein concentration is reversible
c) Likely easier to bring to market than genetic or immune-activating drugs due to clearly defined MOA
8. Ubiquitination machinery is promiscuous – TPD is an induced proximity approach. Bringing two proteins close together does not ensure that they will do the chemistry you want, but since ubiquitination machinery is promiscuous there is a much higher chance it will ubiquitinate the protein if it close enough for long enough
9. Ligands do not need to be particularly strong binders of target vs. SMIs which require extremely high specificity
10. Over longer treatment course, SMIs tend to induce mutations in the binding pocket causing a decreased affinity of the drug to the target, diminished binding efficacy, and therefore loss of clinical efficacy. With TPDs, point mutations are unlikely to reduce the binder’s affinity below the threshold needed for catalytic efficiency, providing efficacy durable to mutations in the clinic
👎 Limitations of TPD:
1. There are limited in vivo studies demonstrating the selectivity and localization of both protein binding elements and E3 ligases in the tissue of interest
2. Heterobifunctional degraders do not look like traditional drugs as most of these compounds violate Lipinski’s rule of five – oral bioavailability of these drugs may be low due low solubility and poor cell permeability
3. Due to the catalytic nature of TPD drugs, traditional methods to evaluate safety and dosing may not be accurate.
a) Different patients may require different doses, which pose challenges to both titration, trial design, and FDA label approval
b) Off target toxicity could be extreme and it may be challenging to predict or detect off-target effects immediately with existing proteomic tools
c) It is unclear what the long-term effects are for this type of treatment and how long unwanted activity could persist
4. Patients being treated with IMiDs for MM have developed resistance to treatment. Based on studies of MM cell lines the mechanism of resistance is thought to be mutation or downregulation of the E3 ligase CRBN. The long-term effects to patient health following the downregulation of an E3 ligase are not well known, and this indicates that TPD drug resistance is possible
5. The current technology is only able to target intracellular proteins that can be degraded by the proteasome. E3 ligases are only found in cells so extracellular proteins (~40% of the proteome) cannot be targeted
6. Canonical ubiquitination requires a surface exposed lysine that is accessible to the E2 ubiquitin conjugating enzyme
a) However, non-lysine ubiquitination has been reported and could inform selection of future ligases to treat in deficient target proteins
7. There is currently little published understanding of optimal design principles for the linker between the E3 ligase binder and the protein target ligand; its flexibility, length, or interactions could dictate molecular proximities of the UPS and target protein, enhancing or limiting catalytic effect. Chemically, the linker must balance a desire to simultaneously minimize steric clash and maximize favorable non-covalent interactions between the E3 ligase and POI when they form a ternary complex
8. What happens when the known therapeutic targets and ligases are exhausted?
a) In-clinic molecules focus on only a handful of E3 ligases (CRBN and von Hippel-Lindau are the most common) and are primarily targeting proteins with well-established small molecule inhibitors and well-established ligands – e.g. “re-drugging the druggable”
b) The feasibility of identifying new E3 ligases and their respective ligands or developing highly specific ligands for potential protein targets that lack well-characterized inhibitors is still unclear. For a long time E3 ligases were thought to be undruggable, which may present challenges for achieving binders sufficient to achieve a proximity-induced approach as well
4. The Parallax View
The commercial success of lenalidomide coupled with the publication of positive interim clinical data from Arvinas (and its <$2.4B Pfizer partnership) demonstrate the near term potential of TPD based technologies. As the first generation of heterobifunctional degraders complete clinical trials, this modality is seeing enormous investment from biopharma and venture capital, signaling that now is the time to pay attention to and invest in TPD. Investing today bears substantial risk, as the TPD modality is under scrutiny and early trials may affect the entire market, but applicability to nearly all disease areas presents a large upside opportunity to match. TPD could prove to be as transformative as the development of mABs.
Apart from developing diversified pipelines to address unmet clinical needs, the companies we have featured in this space are developing discovery platforms built from tangible, differentiated IP assets rather than know-how and snazzy acronyms alone. Leading firms are also continuing to perform and publish fundamental research that expand our understanding of the theoretical scope of these technologies in treating disease. We believe that this will lead to a widening moat for well-established players as the TPD industry becomes more crowded.
At this time, retail investment opportunities are limited to a few companies focusing on heterobifunctional degraders, which depart from the proven monofunctional mechanism of lenalidomide. Firms building TPD 2.0 technologies remain years from the clinic, with investor sentiment likely to follow the near-term success or failure of monofunctional and heterobifunctional trials. If TPD 2.0 is successful, it does not necessarily mean that companies focused currently on monofunctional and heterobifunctional degraders will not be able to leverage their know-how and platforms to carve out a niche—after all, drugs need to be commercialized and pushed to market. Additionally, an underlying scientific concept of TPD is chemically induced proximity. The discovery platforms being developed for TPD could probably be tweaked for the development of alternative chemically induced, proximity-based drugs focused on other disorders that involve chemical modifications, such as acetylation, methylation and phosphorylation.
There could also be spectacular failures with this technology. Updates on TPD drugs have so far been almost unanimously positive, and the near daily articles found on STAT or Endpts about how TPD company X raised >$50MM in an oversubscribed round or how Big Pharma has given TPD company Y >$2 billion in biobucks (Pfizer & Arvinas) are creating a frenzy around the first round of clinical readouts releasing over the next year. Some trials will underdeliver and the gold rush may end, but until modality specific adverse effects are reported, we feel there is little reason to panic about the modality as a whole given the potential for efficacy in previously untreatable areas. Companies furthest along seem to be attempting to de-risk their pipelines by pursing low hanging fruit instead of imaginative approaches to new targets that fully leverage the potential of this novel technology, meaning that the greatest areas of opportunity are likely to come in several years after the modality itself is proven using established disease targets.
5. Our Ranked Shortlist of TPD Players
Note: We will be releasing subscriber-only research reports of the following companies within two weeks, with each around ~1,500 words complete with due diligence on science, strategy, financials, management, and more.
Pick #1: Kymera ($KYMR)
Kymera is our favorite from the four shortlisted because Kymera not only focuses on the current pipeline, but is also building the platform to continuously identify degradable protein through their proprietary platform, while other competitors are more opaque in the elaboration of their platforms. Out of the TPD players, we think Kymera has the highest potential in terms of identifying more novel targets on novel indications. They are building tools to understand the fundamental science and give themselves an edge in developing more inventive TPD drugs (e.g. tissue or mutant specific). Kymera is currently focused on developing drugs that target well known pathways, clearly linked to the progression of a variety of diseases, using a different mechanism of action. Kymera seems the most interested, of these companies, in advancing TPD technology as driven by their all-star management team. At the same time, their pipeline is progressing well and they are going after solid targets and indications, along with a DEL partnership with GSK & HitGEN. Subscribe to read our full $KYMR report.
Pick #2: Nurix ($NRIX)
Nurix is Kymera’s little brother. We cannot quite put a finger on the company’s focus, as Nurix seems to have diversified its pipeline not just about TPD, but also on E3 ligases and has a drug-enhanced CAR-T play as well. Their descriptions of their TPD platform and pipeline place them as a comparable to Kymera. It is not clear if the Sanofi and Gilead collaborations are focused on TPD or inhibition of E3 ligases. Regardless, Nurix has the options to go for 50/50 co-commercialization in U.S. should the drug candidates continue to advance. We suspect they would go for the collaboration approach to accelerate drug to market and to also have earlier funding to establish. At the heart of this company is their proprietary DEL and ability to discover E3 ligases (invested and built from scratch and scaled up their DNA library after 8 years). Arvinas and Kymera also have their own partnered DELs but but they don’t emphasize it nearly as much as Nurix. Thus, Nurix seems to focus on advancing the underlying science, but is also diverging from solely TPD into several potentially rewarding tangents. From the outside it seems chaotic and the company looks like a low budget hybrid of Plexium, Iovance, and Kymera with the connective tissue being a shared drug-discovery platform. Subscribe to read our full $NRIX report.
Pick #3 (Tied): Arvinas ($ARVN)
Arvinas has the the first-mover advantage and most advanced pipeline so their success will color how a more general audience views the technology. The interim data from their two trials is not amazing, and does not demonstrate how this modality could be a huge breakthrough, though their neuroscience division might have some hidden gems. With a mega deal from Pfizer, Arvinas seemed to be overly satisfied with their current PROTAC technology and in our view not investing enough into its discovery engine to sustain its target discovery process. Previously, Arvinas partnered with Microceutics for its DEL (later acquired by Hotspot Therapeutics) so it is unclear how much of Arvinas’ current DEL is proprietary vs. outsourced. While it would have been delightful to see ARVN be more ambitious with its targets through PROTAC technology, being the first company in this area also implies higher risk so it is understandable for ARVN to pick validated targets like estrogen receptor, which was further validated through its phase 1 trial and when Pfizer inked co-commercialization deal and equity investment. This would also set a precedent for other big pharmas to do the same for their respective protein degraders investments.
Another concern that we had was that the founder of Arvinas, Craig Crews, who’s currently sitting on the scientific advisory board, recently founded a new company called Halda Therapeutics (private, ~20 people employed) which may limit the future scope of Arvinas’ work. As of now, Halda Therapeutics remains a black box to us as investors, but we did note that they have hired multiple former Arvinas employees to high-level positions. Patent application US20200268897 is assigned to Halda Therapeutics and mentions “bifunctional compounds that efficiently dephosphorylate certain phospho-activated target proteins” in the Abstract. It seems Halda is focused on using chemically induced proximity technology to chemically modify the POI. The existence of Halda suggests that Arvinas will not expand to chemically induced proximity techniques that are not directly related to degradation of the POI, and is why we think the upside is not as bright as we’d like. Subscribe to read in full.
Pick #3 (Tied): C4 Therapeutics ($CCCC)
It looks like they were so focused on derisking that they wound up with an uninspired pipeline. Their short term prospects appear to be very good. They do not seem like they are trying to advance the technology. They will probably continue to ride the wave and benefit from being an early adopter of TPD technology. C4’s targets are good choices for targeted protein degradation but they are not novel nor exciting. Subscribe to read our full $CCCC report.
Bonus: Monte Rosa Therapeutics ($GLUE)
At the time of writing, Monte Rosa ($GLUE), a TPD biotech, went public and currently has a market cap of around $1 billion. They are focused on developing monofunctional degraders. Monte Rosa is doing something different and provides the ability to diversify across TPD technologies and for that reason warrants a closer look. We will publish a more detailed report of Monte Rosa for subscribers that will be released mid-August and incorporate information released after the conclusion of the quiet period.
Select readings on TPD:
Next month: CD47 or CAR-T… or let us know what you’d like to read about.
Disclaimer: Biotech investing is inherently risky. Our post is for informational purposes only, published to the best of our knowledge and understanding. We accept no liability for any potential direct or indirect losses as a result of our research and views. The reader bears full responsibility for their investment decisions. We reserve every right to adjust our positions without notice.
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To understand how SMIs work, think of a protein in the body as door lock made of atoms, programmed to perform a task when it encounters a molecule that matches the shape of the lock — a metaphorical key. For example, you may have heard of SARS-COV-2’s “key,” called Spike, which fits the ACE2 protein lock in your body’s cell membranes, giving it unauthorized access to wreak havoc! The trouble with small molecule inhibitors is that they must bind directly to target proteins in a way that either blocks the protein’s active site — like putting the key into the lock and breaking it off— or bind to alternate sites that cause a conformational change in the shape of the target protein — like reprogramming the pins of the lock so that it will no longer accept the original key.
“Method for reducing the level and/or activity of a target protein in a eukaryotic cell via activation of ubiquitination of the target protein wherein the cell is contacted with the compound having a ubiquitination recognition element covalently linked to a target protein binding element. The ubiquitination and recognition element can bind to either the E3 or E2 elements of the ubiquitination system and the target protein binding element is able to bind specifically to the target protein.”