HC278

Note that optimal concentrations can be dependent on the assayed cell type and should be tested.

This compound could be used to probe TEAD1/3 biology in cells but with a lot of care. 1) The concentration should be kept at or below 50 nM; based on the data presented in the 10.1016/j.heliyon.2024.e37829 (Fig. 1E') at 200 nM, levels of TEAD2/4 also begin to go down. The possibility that HC-278 also targets TEAD2/4 is also seen in Fig. 2 data. Using proteasome inhibitor, and TEAD-binding ligand rescues degradation of all TEADs, especially TEAD2. 2) Negative control compounds: based on the data in Fig. 2E, HC278-Neg1 is not a suitable negative control as it, based on visual inspection of the blots, it does cause degradation (compared to DMSO); HC278-Neg2 seems like a better NC compound.

HC278 can be used as a dual-selective degrader of TEAD1 & TEAD3. At higher concentrations (>500nM) degradation of TEAD-family members TEAD 2 & 4 can also be seen. HC278-Neg2 is recommended as a suitable negative CRBN control while the POI negative control HC278-Neg1 still shows degradation and target engagement. Stronger degradation of TEAD1 compared to TEAD3 was shown by proteomics experiment in NCI-H226 cells. The user of the probe is advised that selectivity for degradation is shown but no inhibition data of HC278 for all TEAD-family members is given.