Dysregulation of RAS–MAPK signaling is a driver of many solid cancers. Hence, targeting major factors of this pathway is a key area of interest in cancer therapeutics. Strategies for targeting the RAS–MAPK pathway have focused on single agents — for instance, inhibitors of MEK kinases (such as trametinib and cobimetinib) and RAF kinases (such as tovorafenib and belvarafenib). However, approaches for simultaneously targeting multiple nodes along the pathway — for example, through the dual RAF–MEK inhibitor avutometinib — have also been developed. Nevertheless, these efforts have been largely associated with limited efficacy due to the emergence of resistance, as well as severe toxicity-associated dose reductions and treatment interruptions. In a paper published in Cancer Discovery, Ryan et al. present NST-628, a pan-RAF–MEK ‘molecular glue’ that may overcome limitations posed by previous inhibitors that target RAS–MAPK signaling factors.

The authors identified NST-628 as a potent pan-RAF–MEK non-degrading molecular glue that inhibited the phosphorylation and activation of MEK by RAF. Detailed characterization of this inhibitor and its mode of action demonstrated that it engaged all RAF isoforms in both active conformations and inactive conformations, preventing RAF heterodimer formation and inhibiting RAF–MEK complexes in an inactive conformation.