pixantrone-based PROTAC

Pixantrone-based PROTAC is an experimental proteolysis-targeting chimera (PROTAC) designed to induce the degradation of the KRAS protein, specifically targeting the KRAS(G12D) mutant. The molecule consists of pixantrone, identified through in silico screening as a potential KRAS-binding warhead, tethered via alkyl linkers to pomalidomide, which recruits the Cereblon (CRBN) E3 ubiquitin ligase. Developed for the treatment of pancreatic cancer, preclinical evaluations demonstrated that these PROTACs had limited efficacy in degrading KRAS and failed to significantly impact downstream MAPK signaling or cell viability. Consequently, the development of this specific pixantrone-based design was not pursued further in favor of alternative warhead candidates.