Necroptosis and Ferroptosis
Necroptosis and ferroptosis are newly discovered modes of regulated necrosis. Necroptosis is regulated by RIP kinase 1 (RIP1) and plays a critical role in several inflammatory diseases. Furthermore, RIP1 has functions in inflammation that go beyond its role in necroptosis. Recently, we developed a very potent RIP1 inhibitor from a kinase inhibitor that is in the clinic. Also, ferroptosis, an iron-regulated form of necrosis, plays an important role in several diseases, such as ischemia-reperfusion injury. We recently described a metabolically stable and potent ferroptosis inhibitor.24 Currently, we have further optimized pharmacokinetic properties and are moving toward in vivo proof of concept studies.
24. Hofmans, S.; Vanden Berghe, T.; Devisscher, L.; Hassannia, B.; Lyssens, S.; Joossens, J.; Van Der Veken, P.; Vandenabeele, P.; Augustyns, K. Novel Ferroptosis Inhibitors with Improved Potency and ADME Properties. J. Med. Chem. 2016, 59, 2041-2053.
In this project we are searching for Atg4B inhibitors with the aim to interfere with autophagy in atherosclerosis and in cancer models.25 One compound already demonstrated promising properties in an in vivo colon cancer model.
25. Cleenewerck, M.; Grootaert, M. O. J.; Gladysz, R.; Adriaenssens, Y.; Roelandt, R.; Joossens, J.; Lambeir, A. M.; De Meyer, G. R. Y.; Declercq, W.; Augustyns, K.; Martinet, W.; Van der Veken, P. Inhibitor screening and enzymatic activity determination for autophagy target Atg4B using a gel electrophoresis-based assay. Eur. J. Med. Chem. 2016, 123, 631-638.