From basic research to drug precursor

AKT Inhibitor Borussertib

© Daniel Rauh

Since the discovery that serine/threonine kinase AKT, also called protein kinase B, can act as a proto-oncogene, there has been great interest in this kinase. AKT plays a central function in the regulation of various cellular processes such as metabolism, cell-growth, - survival and protein synthesis. As a result, the PI3K/AKT pathway is active in several human cancer types, contributing to tumor development, progression and metastasis. However, therapies in which AKT inhibitors are used often have limitations in the accuracy effecting the right target or are associated with dose-limiting effects.

Professor Daniel Rauh from the Technical University of Dortmund, e:Med alliance SMOOSE, succeeded in working with physicians from Essen and Bochum to develop a new AKT inhibitor, which already shows efficacy in pancreatic cancer. The researchers were able to identify the first crystal structure of AKT1 in the complex with the new covalent allosteric AKT inhibitor Borussertib, providing important insights into the structural basis of inhibition. Initial preclinical studies with the inhibitor resulted in strong anti-proliferative activity in cancer cell lines showing genetic changes within PTEN, PI3K and RAS signaling pathways. Thus, Borussertib interferes with the uncontrolled proliferation of cancer cells.

First in vivo experiments in a mouse model showed the similar effects of the inhibitor. By combining Borussertib with the anti-proliferative inhibitor Trametinib, the researchers were able to induce anti-tumor effects in xenograft models of human pancreatic and colon cancer. In these models, human tumor cells are transplanted into mice, which then form a human tumor. This xenograft allows the examination of the human tumor in a natural microenvironment. Pancreatic cancer is currently insufficiently treatable due to its aggressiveness and high resistance.

The focus of further research is now on optimizing the new drug to further develop it for clinical testing and to be able to use it in the future in the treatment of cancers such as pancreatic or colon cancer.