Tetracyclic pyrazinocarbazole derivatives as YAP-TEAD pathway inhibitors with activity in a melanoma lung colonization model.

Direct pharmacological disruption of the YAP-TEAD transcriptional complex is a promising strategy for Hippo pathway-driven cancers, but chemically tractable small-molecule chemotypes with in vivo activity remain limited. Here, we describe the optimization of a pirlindole-derived tetracyclic pyrazinocarbazole scaffold to improve YAP-TEAD inhibitory activity. Structure-activity relationship studies of 37 derivatives identified N3 sulfonyl substitution as a key feature associated with enhanced activity, leading to the identification of compound 9d as the most active analogue in this series. In cell-based assays, compound 9d inhibited YAP-TEAD-dependent transcriptional activity more effectively than the parent scaffold. In a B16-F10 melanoma lung colonization model, 9d reduced pulmonary tumor burden in a dose-dependent manner. These findings support compound 9d as a lead scaffold for further development of YAP-TEAD pathway inhibitors, while direct target-engagement and pharmacodynamic studies will be required to define its binding mode and mechanism of action.