Periodic Reporting for period 1 - proCOLON (First-in-class beta-catenin inhibitor as treatment for colorectal cancer)
Periodo di rendicontazione: 2022-05-01 al 2023-10-31
With more than 1.9 million new cases and 935,000 related deaths in 2020, colorectal cancer (CRC) is the third most common cancer in men and the second in women. While surgery is the main treatment option for lower grade CRC, patients with unresectable lesions are treated with chemotherapy. Related therapies are associated with severe drawbacks, such as systemic toxicity, low response rate, and unpredictable resistance. Molecular targeted therapies have emerged as a promising strategy to specifically target cancer cells. For CRC, the inhibition of the Wnt signalling pathway has moved into the focus of novel therapeutic approaches as it is hyperactivated in 80% of all cases. Within the pathway, the protein beta-catenin is considered a particularly attractive target. However, classic small molecule targeting strategies have failed to provide any approved drugs that inhibit beta-catenin so far.
We have identified a family of peptidomimetic agents that bind beta-catenin and inhibit its interaction with the TCF/LEF transcription factors. For the first time, it was possible to obtain a crystal structure of a synthetic molecule bound to a therapeutically very attractive site on beta-catenin. In addition, we have confirmed cellular activity of these inhibitors verifying selective inhibition of the Wnt signalling pathway. These findings provide the ideal starting point for the development of novel therapeutics for Wnt-dependent cancers, in particular for CRC. These first-in-class inhibitors will provide the basis for the development of therapeutics that selectively inhibit oncogenic Wnt signalling thereby affecting the viability of corresponding cancer cells. This can enable targeted therapies for Wnt-dependent forms of CRC. Within this project we further increased the readiness level of these inhibitors with respect to scientific and business aspects.
We have identified a family of peptidomimetic agents that bind beta-catenin and inhibit its interaction with the TCF/LEF transcription factors. For the first time, it was possible to obtain a crystal structure of a synthetic molecule bound to a therapeutically very attractive site on beta-catenin. In addition, we have confirmed cellular activity of these inhibitors verifying selective inhibition of the Wnt signalling pathway. These findings provide the ideal starting point for the development of novel therapeutics for Wnt-dependent cancers, in particular for CRC. These first-in-class inhibitors will provide the basis for the development of therapeutics that selectively inhibit oncogenic Wnt signalling thereby affecting the viability of corresponding cancer cells. This can enable targeted therapies for Wnt-dependent forms of CRC. Within this project we further increased the readiness level of these inhibitors with respect to scientific and business aspects.
The scientific core activities involved the synthesis of additional inhibitors and test their affinity for the target protein beta-catenin. This resulted in a detailed structure-affinity relationship (SAR) that now guides the further development process. Examples of tested aspects and scaffolds involve i) alternative macrocyclization strategies, ii) sequence truncations, and iii) extensive amino acid variations. As a result, we have identified improved macrocyclic and linear inhibitor versions. Most notably, a macrocyclization strategy was implemented that provides inhibitors with increased yields and purity while conserving high target affinity. In addition, a patentability search was performed to guide future development efforts.
The most novel and relevant findings involve an improved macrocyclization approach that give rapid and reliable synthetic access to inhibitors. In addition, a sequence was identified that does show remarkable target affinity in its linear form which opens the door to the development of novel inhibitor scaffolds. In the course of the project, we also initiated collaborations towards alternative strategies to enable cellular uptake of the inhibitors, which broadens potential fields of applications.