H122 is a PROTAC degrader for TEAD that degrades TEAD1 with a DC50 of 3 nM. H122 exhibits good affinity to TEAD2, TEAD3, and TEAD4 with K i values of 2.0, 3.6 and 1.6 nM, respectively. H122 relies on binding to TEAD1 and CRBN, functional E3 ligase activity, and a functional proteasome for degradation.H122 induces degradation of TEAD3 and forms a ternary complex with TEAD4 and CRBN/DDB1 to mediate degradation.H122 downregulates expression of Myc target genes. H122 exhibits antitumor efficacy in MSTO-211H mouse xenograft models.H122 can be used for the research of malignant mesothelioma [1]. (Pink: TEAD ligand; Blue: Cereblon ligand; Black: linker).
In Vivo, H122 (Compound 40) (10-50 mg/kg; i.p.; daily for 21 days, single injection) significantly degrades TEAD1 in MSTO-211H xenograft tumor tissues and inhibits tumor growth in a dose-dependent manner, with the 20 mg/kg daily i.p. dose yielding a T/C value of 37.7% and no associated body weight loss[1].
In Vitro, H122 (Compound 40) binds potently to human TEAD1, TEAD2, TEAD3, and TEAD4 proteins in vitro, with highest affinity for TEAD1 (Ki=0.3 nM)[1]. H122 promotes the formation of a ternary complex between TEAD4 and the CRBN/DDB1 E3 ligase complex in vitro, a key step for PROTAC-mediated degradation[1]. H122 (4 days) potently inhibits the growth of MSTO-211H and NCI-H226 cancer cell lines in vitro, with higher activity in NCI-H226 cells (IC50=0.6 nM)[1]. H122 (10-100 nM; 1-24 h) potently and rapidly degrades TEAD1, TEAD3, and TEAD4 proteins in MSTO-211H and NCI-H226 cancer cells, with TEAD1 degradation DC50=3.0 nM in MSTO-211H cells[1]. H122 (0.1-1000 nM; 4 h) suppresses the expression of TEAD target genes in MSTO-211H cells in vitro in a dose-dependent manner, confirming inhibition of TEAD transcriptional activity[1]. H122 (100 nM; 4 h) induces widespread transcriptional reprogramming in MSTO-211H cells, with significant downregulation of Myc target genes and other TEAD-associated oncogenic genes[1]. H122 (1-1000 nM; 24 h (cell cycle), 48 h (apoptosis)) induces G1 cell cycle arrest and apoptosis in MSTO-211H cancer cells, contributing to its antiproliferative activity[1].
References:
[1]. Lu Y, et al. Selective Degradation of TEADs by a PROTAC Molecule Exhibited Robust Anticancer Efficacy In Vitro and In Vivo. J Med Chem. 2025;68(5):5616-5640.
In Vivo, H122 (Compound 40) (10-50 mg/kg; i.p.; daily for 21 days, single injection) significantly degrades TEAD1 in MSTO-211H xenograft tumor tissues and inhibits tumor growth in a dose-dependent manner, with the 20 mg/kg daily i.p. dose yielding a T/C value of 37.7% and no associated body weight loss[1].
In Vitro, H122 (Compound 40) binds potently to human TEAD1, TEAD2, TEAD3, and TEAD4 proteins in vitro, with highest affinity for TEAD1 (Ki=0.3 nM)[1]. H122 promotes the formation of a ternary complex between TEAD4 and the CRBN/DDB1 E3 ligase complex in vitro, a key step for PROTAC-mediated degradation[1]. H122 (4 days) potently inhibits the growth of MSTO-211H and NCI-H226 cancer cell lines in vitro, with higher activity in NCI-H226 cells (IC50=0.6 nM)[1]. H122 (10-100 nM; 1-24 h) potently and rapidly degrades TEAD1, TEAD3, and TEAD4 proteins in MSTO-211H and NCI-H226 cancer cells, with TEAD1 degradation DC50=3.0 nM in MSTO-211H cells[1]. H122 (0.1-1000 nM; 4 h) suppresses the expression of TEAD target genes in MSTO-211H cells in vitro in a dose-dependent manner, confirming inhibition of TEAD transcriptional activity[1]. H122 (100 nM; 4 h) induces widespread transcriptional reprogramming in MSTO-211H cells, with significant downregulation of Myc target genes and other TEAD-associated oncogenic genes[1]. H122 (1-1000 nM; 24 h (cell cycle), 48 h (apoptosis)) induces G1 cell cycle arrest and apoptosis in MSTO-211H cancer cells, contributing to its antiproliferative activity[1].
References:
[1]. Lu Y, et al. Selective Degradation of TEADs by a PROTAC Molecule Exhibited Robust Anticancer Efficacy In Vitro and In Vivo. J Med Chem. 2025;68(5):5616-5640.