Captor reports
Beta-Catenin: An Elusive Target - New Chemistry as a Skeleton Key for Oncological Drugs

 

Beta-Catenin: A Key, Yet Elusive, Target in Oncology

 

Beta-catenin is a protein of fundamental importance for cell function, playing a crucial role in the Wnt signaling pathway. This pathway is frequently dysregulated in many types of cancers, leading to excessive beta-catenin activity. As a result, genes responsible for the growth and proliferation of cancer cells are activated, which contributes to tumor development. Although beta-catenin is one of the best-understood cancer-related proteins and a key molecular target, it has long remained "undruggable" - extremely difficult to target with small-molecule drugs. Its complex structure and lack of distinct binding pockets have hindered the development of effective inhibitors. As one of the most important therapeutic targets in modern medicine, many researchers have questioned whether inhibiting beta-catenin is even possible.

Beta-catenin plays a significant role not only in cancer development but also in many other biological processes, so its proper regulation is essential for maintaining homeostasis. Disruptions in the activity of this protein can lead to serious health consequences, including the development of malignant tumors. Captor Therapeutics, an innovative biopharmaceutical company, is using modern technologies for targeted protein degradation (TPD) to develop breakthrough drugs aimed at beta-catenin and other previously "undruggable" proteins. This approach allows for the elimination of harmful protein molecules responsible for disease progression, opening up new possibilities in oncological and autoimmune treatments. Using its proprietary research platforms, the company is seeking new therapeutic opportunities, providing patients with access to innovative therapies where previous options have been insufficient.

A Breakthrough Discovery by Captor Therapeutics

Captor Therapeutics has made a significant breakthrough in beta-catenin research by developing a crystallographic platform that enables the precise evaluation of compounds that bind to the beta-catenin armadillo (BC-ARM) domain. This innovative technology allows for the analysis of the spatial arrangement of a protein's atoms and ligand molecules, which significantly accelerates the identification and optimization of drug candidates.

As part of its research, Captor standardized the protein production protocol and conducted extensive biophysical studies using methods such as Surface Plasmon Resonance (SPR) and Differential Scanning Fluorimetry (DSF). This allows for the high-throughput screening of beta-catenin's interactions with various molecules, which is a crucial step in the development of small-molecule drugs.

A key achievement was obtaining co-crystal structures of beta-catenin with newly discovered binding sites, which differ from previously known interaction sites with transcription factors. The use of a chemical fragment library enabled the identification of a new binding hotspot that could serve as a target for bispecific degraders like PROTACs. Optimizing the beta-catenin construct has allowed for the reproducible acquisition of high-quality crystals, which greatly facilitates further crystallographic studies. We are confident that our research represents a fundamental step toward developing novel cancer treatment strategies by targeting this previously "elusive" target.

New Perspectives in Cancer Treatment with Targeted Protein Degradation

The platform developed by Captor Therapeutics is a powerful tool for designing new drugs that can modulate beta-catenin activity and effectively eliminate this protein from cancer cells. The targeted degradation of beta-catenin is particularly important in the treatment of cancers where the Wnt pathway is overactive.

The most important indications include:

• Colorectal cancer: Beta-catenin plays a fundamental role in the pathogenesis of most cases of this cancer.
• Liver cancer: Activation of the Wnt/beta-catenin pathway is frequently observed in hepatocellular carcinoma, making it an attractive therapeutic target.
• Immuno-oncology: Preliminary studies indicate that beta-catenin modulation can influence the tumor microenvironment and immune response, opening up new possibilities for combination therapies.

Such research makes it possible to develop drugs that reduce the proliferation of cancer cells and tumor growth. This, in turn, will translate into better treatment outcomes and improved quality of life for patients.

Structural Studies: The Driving Force in the Fight Against Cancer

Expanding knowledge of key hotspots in cancerous diseases, such as beta-catenin, can be applied in the growing oncology therapeutics market.

Colorectal Cancer (CRC) Colorectal cancer is the second most common cancer in the world and one of the leading causes of cancer-related deaths, as confirmed by global statistics - with close to 0.9 million deaths annually. In Poland, over 18,000 new cases of CRC are diagnosed annually, with the number of deaths reaching nearly 12,000. This accounts for approximately 12.5% of all oncological deaths in the country. Moreover, an increase in cases is being observed among people under 50, which poses a serious challenge to the healthcare system. The global market for colorectal cancer therapies in 2024 is estimated at around USD 12.79 billion, with a projected growth to approximately USD 19.95 billion by 2034, at an annual growth rate (CAGR) of 4.55%. This shows the immense potential and demand for new drugs, especially those using innovative approaches such as targeted protein degradation.

Liver Cancer (HCC) Liver cancer is the sixth most common cancer but also the third most frequent cause of cancer-related deaths worldwide. This disease occurs more often in men, mainly after the age of 60, with chronic viral hepatitis and cirrhosis being the main risk factors. The global market for liver cancer drugs is valued at approximately USD 3.67 billion in 2024, with a projected growth to USD 9.81 billion by 2030 (CAGR 17.9%). This is one of the fastest-growing segments of the oncology market. The high mortality associated with liver cancer (over 830,000 deaths annually) confirms the urgent need to develop more effective drugs that can reduce tumor growth and improve patient survival.

Summary

Beta-catenin remains one of the most important, yet most difficult, molecular targets to treat in oncology. Captor Therapeutics' research and the development of targeted protein degradation technology have significantly expanded pharmacological possibilities in this area. The developed crystallographic platform has allowed for a detailed understanding of beta-catenin structures and its interactions with small molecules. The published structure opens the door to creating new drugs capable of effectively eliminating this protein from cancer cells.