Thrombosis including venous thrombosis and pulmonary embolism with an annual incidence of about 1 in 1,000 adults is a major threat for human health, in particular at old age. To counteract blood clotting, patients take blood-thinning medication, which, however, can cause severe side-effects such as bleeding (hemorrhage). The lipid kinase PI3KC2α has been found to potently modulate thrombosis by regulating the function of blood platelets that are at the heart of initiating the blood clotting mechanism e.g. in response to high blood pressure or atherosclerosis. PI3KC2α, therefore, is a powerful target for the development of novel anti-thrombotic drugs. However, so far no specific inhibitor of PI3KC2α has been described.
Dr. Wen-Ting Lo from the research group of Professor Volker Haucke in close collaboration with medicinal chemist Dr. Marc Nazaré and his team, researchers from Toulouse, and the Screening Unit of the FMP (led by Dr. Jens Peter von Kries) has now developed and characterized the first PI3KC2α inhibitors. As a result of extensive chemical optimization studies the researchers succeeded in tweaking the selectivity of the inhibitors over the entire kinome, in particular against all other lipid kinases. Tne of these compounds termed PITCOIN3 displays particularly striking selectivity for PI3KC2α and is shown to potently impair platelet membrane remodeling and thrombus formation.
“This breakthrough development has only been possible because of our earlier structural studies on PI3KC2α,” comments Wen-Ting Lo, the first author of the study just published in Nature Chemical Biology. Marc Nazaré adds “that the unexpected non-classical binding mode of the PITCOIN inhibitors reveals a promising new blueprint for the development of related drug leads. The PITCOINs may also be important tools to help other researchers to probe and uncover unknown functions of PI3KC2α.” “The antithrombotic effect of the PITCOIN inhibitors counteracts thrombosis via effects on the internal membrane structure of platelets, not by blocking their activation, thereby opening an improved therapeutic window,” emphasizes Volker Haucke.
The reported findings could open new possibilities for the treatment of thrombosis and cancer, as demonstrated by the ability of PITCOINs to interfere with the migration of breast cancer cells in vitro.
“This paper served as a template for our film. It illustrates very well how many groups work closely together in a project. But in what way should we tell the process of collaboration in three minutes? Models, brilliant minds, target structures, equipment, methods? That sounds like a script for a new James Bond case. So we produced a trailer. Enjoy watching it!” - Silke Osswald, Public Relations Officer at FMP
Text: Silke Oßwald
The article was published in Verbundjournal 119 | 2022 with the focus on "30 years of FVB."
