VT103

SPR data or similar demonstrating the direct interaction between VT103 and TEAD1 (vs TEAD2-4) would be desirable. Also, CETSA in cells would be a useful addition, as well as some selectivity screens against common targets.

This is a solid probe for TEAD1 that functions by inhibiting TEAD1 autopalmitoylation, and, thus, inhibiting interaction between TEAD1 and YAP-TAZ. In terms of probe validation, although selectivity over other TEADs has been shown (although not biophysically/biochemically quantified), proteomic selectivity has not been demonstrated. Although there is solid evidence that VT103 works via the proposed mechanism and exerts its effects via inhibiting TEAD1 autopalmitoylation and, thus, interfering with YAP-TAZ binding to TEAD1, in-cell target engagement has not been formally shown. Also missing are knockout experiments that show that the phenotype does not occur in the absence of the target. Overall, given that VT103 exhibits TEAD1 isoform selectivity and shows good in vivo performance, I am comfortable recommending the use of this probe at concentrations suggested, provided the analysis is accompanied by additional controls (knock-outs and knock-downs) and using orthogonal strategies and negative control compound VT106. NOTE ON THE NEGATIVE CONTROL COMPOUND: VT106 is not formally a negative control for VT103 as it is a compound from a different chemical class. Development of a more closely related negative control compound is recommended. NOTE ON CLASSIFYING THIS COMPOUND (AND OTHERS IN THIS SPACE) AS PPI INHIBITORS: these compounds are competitive inhibitors of autopalmitoylation reaction. They do disrupt TEAD binding to YAP-TAZ but that is an indirect effect given that TEAD palmitoylation is required for YAP-TAZ binding. I recommend not referring to these as PPI inhibitors.