Protein degradation platforms have revolutionized drug discovery aimed at undruggable targets. Biopharmaceutical companies around the world have engaged in the protein degradation field, with the hope of leveraging the capabilities of these coumpounds to successfully design drugs to treat diseases like cancer and neurodegenerative disorders.
The discovery of the ubiquitin and proteolysis – protein degradation – mechanisms in the 1980s garnered attention for the potential of targeted protein degradation as a novel drug modality. Since then, companies have been attempting to apply these functions for therapeutic research.
With more biopharmas setting foot into the drug discovery arena, here are six companies, presented in alphabetical order, conducting some interesting research in the field of protein degradation.
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Arvinas
As tackling undruggable targets can be quite difficult, U.S.-based company Arvinas focuses on a novel approach in induced proximity to initiate the degradation of target proteins.
The company’s technology, PROTAC – protein degraders that tag proteins by binding to them weakly – targets the disease-causing proteins, following which, copies of proteins are sequentially degraded. For the treatment of central nervous system (CNS) diseases, the platform successfully underwent preclinical trials to exhibit its efficacy – its ability to penetrate the blood-brain barrier. Depending on the disorder, PROTAC can be administered intravenously and even orally.
Arvinas’ PROTAC-based pipeline consists of more than 12 drug candidates, which are being studied in immuno-oncological and neuroscience research. Its lead candidate, ARV-471, is an investigative oral protein degrader that targets the estrogen receptor (ER) for the treatment of breast cancer. The signaling from the ER – which is a hormone receptor – can drive metastatic breast cancer.
As 80% of breast cancer cases are ER positive, Arvinas’ focus on targeting the signaling could be therapeutically efficacious in patients where aggressive manifestations of the disease continue to progress despite hormone and chemotherapy treatments. ARV-471 is being developed in collaboration with global pharmaceutical Pfizer.
Founded in 2013, and headquartered in Connecticut, the company has received more than $111 million in investments, with the latest funding raised in series C round in 2018.
C4 Therapeutics
Set up in the biotech hotspot of Cambridge, Massachusetts, C4 Therapeutics explores the field of targeted protein degradation (TPD) to eliminate disease-causing proteins, tending to the ubiquitination process, in order to harness its drug discovery potential.
Its proprietary technology, the C4T Target ORiented ProtEin Degrader Optimizer (TORPEDO) platform synthesizes small molecules that are designed to specifically target disease-causing proteins considered to be undruggable targets.
Since the company’s inception in 2016, it has been collecting and analyzing data of numerous protein degrader molecules, and with the help of computational models, it has observed the role of these degraders in attacking target proteins, enabling the platform to be optimized to improve its specificity. The platform has two kinds of degraders – one that binds to E3 ligases to initiate the binding of E3 ligase to target proteins, while the other binds to the disease-causing target protein as well as E3 ligase on either side.
In its pipeline, the protein degradation company specializes in the treatment of cancer. One of its drug candidates, CFT7455, targets the expression of IKZF1/3 for relapsed or refractory multiple myeloma (RRMM) and non-Hodgkin’s lymphomas (NHL), and is currently in its early-stage of clinical trials. Other drug candidates also focus on solid tumors, and are in various stages in development, and preclinical and clinical trials.
Having completed five rounds of funding, the company has raised $273.8 million, with its latest investment secured in August 2022. Venture capitals Taiwania Capital Management Corporation and Lightchain are its most recent investors.
Fluidic Analytics
Situated in Cambridge, U.K., Fluidic Analytics has set up a protein interactions lab that observes protein interactions, including those targets that are challenging and undruggable.
The company’s research mainly focuses on neurodegenerative disorders and infectious diseases, particularly COVID-19.
Its Fluidity One system, which is based on microfluidic diffusional sizing (MDS) – a method to measure the size of particles – is utilized to characterize protein interactions. The company acknowledges that there is a need for a novel approach to target CNS diseases such as Alzheimer’s and Parkinson’s diseases as they are caused by an accumulation of misfolded protein; opening pathways to protein degrader-based treatment options.
As 99% of Alzheimer’s drug trials have failed in the past 10 years, according to Fluidic Analytics, the company plans to address challenges through its assay – biochemical tests on a cellular level – for researchers to study how viable drug candidates are with regard to their interaction with their corresponding targets.
Founded a decade ago, the company has obtained more than $40 million in funding over the past 10 years in four rounds, with its most recent investors being U.S. manufacturer BGF Industries and investment firm Delin Ventures, among a total of eight investors.
NEOsphere Biotechnologies
Barely two years old, NEOsphere Biotechnologies was established in Germany in 2022, and is yet another company with a keen interest in the potential for targeted protein degradation to address unmet medical needs in patients.
TPD uses the cell’s waste disposal system as its method to destroy disease-causing proteins. The catalytic degraders are small molecules that redirects E3 ubiquitin ligases – a protein that regulates homeostasis, a process that stabilizes the body’s physiochemical conditions for its best chance at survival – to the substrate proteins to form a complex that modifies the substrate, which is then degraded. This technology beats other available platforms in not requiring active binding sites to exert its effect.
For its efforts in drug discovery, the company studies the scope for TPD using mass spectroscopy, which is an analytic tool used to measure the mass of a molecule.
The company closed Series A funding for further development of its technology in July 2022.
Origami Therapeutics
Based in California since 2016, the company’s platform ORICISION, which focuses on protein degradation, enables the discovery of protein degraders and conformation correctors, to uncover protein structure and target abnormal protein function.
The drug discovery platform, which has the potential to prevent the spread of disease-causing proteins, is being studied in the treatment of neurological disorders like Alzheimer’s disease, Huntington’s disease and Parkinson’s disease among others.
Huntington’s disease is a rare genetic disorder where the nerve cells in the brain become damaged, and as a result, can affect the movement, cognition and mental health of an individual.
For its treatment, Origami’s technology is able to limit the formation of toxic mutant HTT protein fragments, which are released because of the misfolding of the HTT protein caused by reduced proteostasis – a process involved in protein regulation in the cell.
While the platform seems promising, all the candidates in its pipeline are yet to undergo preclinical testing to assess efficacy and risk.
Initially self-funded, the discovery-stage company has received funding from startup accelerator Y Combinator, and raised its first round in 2022.
Ranok Therapeutics
Headquartered in Hangzhou, China, Ranok Therapeutics is a preclinical-stage biotech company that is focused on the role of chaperone proteins, which mediate the proper folding of proteins to regulate proteostasis. These chaperone proteins can also direct proteins towards the ubiquitin-proteasome system – which is responsible for the degradation of unwanted proteins.
Its product, Chaperone-mediated Protein Degradation/Degrader (CHAMP), can loosely bind the target and the chaperone protein complex together, by connecting to both elements on either side, in order to stimulate target degradation. The technology has been designed to treat cancer, and has proven its safety while targeting solid tumors.
In August 2022, Ranok Therapeutics announced the start of patient dosing in clinical trials for its first-in-class protein degrader drug RNK05047, which is an application of CHAMP’s technology.
The protein degradation company has obtained a total of $50 million over two rounds of series funding with the latest being in 2021, and their most recent investors are Wu Capital and Shanghai Healthcare Capital.