TED-690 is a potent, heterobifunctional TEAD·YAP/TAZ PROTAC degrader, degrades YAP, pYAPS127, and active YAP protein levels with DC50 values of 0.1 μM (Dmax=57%), 0.1 μM (Dmax=80%), and 0.01 uM (Dmax=80%) in MDA-MB-231 cells, also degrades partners YAP and TAZ.
TED-690 reduced YAP, pYAPS127, and active YAP protein levels, with DC50 values of 0.2 ± 0.2 μM (Dmax = 61%), 0.3 ± 0.3 μM (Dmax = 62%), and 0.03 ± 0.02 μM (Dmax = 61%), respectively, in YAP-amplified small cell lung cancer cell line NCI-H841.
TED-690 degraded pYAPS127 and TEAD with nanomolar DC50 values of 0.03 ± 0.04 μM (Dmax = 70%) and 0.02 ± 0.03 μM (Dmax = 71%), respectively, in triple-negative breast cancer cell line MDA-MB-468.
TED-690 reduced TEAD and TAZ protein levels with DC50 of 0.4 ± 0.1 μM (Dmax = 63%), and TAZ with DC50 of 0.4 ± 0.3 μM (Dmax = 66%) in MDA-MB-468 and TMD-231 cell lines.
TED-690 demonstrated time-dependent degradation, reducing YAP, TEAD, and TAZ protein levels in MDA-MB-231 cells with degradation half-lives of 10.1 ± 1.9 h, 9.6 ± 1.4 h, and 9.7 ± 1.4 h, respectively.
TED-690 inhibited YAP-TEAD transcriptional activity and cell survival.
TED-690 binds to the TEAD lipid pocket have the potential to degrade not only TEAD, but also its binding partners YAP and TAZ.