TX2-121-1

TX2-121-1 is a bifunctional hydrophobic tag Her3 degrader and also a Her3 inhibitor with an IC₅₀ of 49 nM. TX2-121-1 covalently binds to Cys721 of Her3, induces Her3 degradation via the Hsp70/Hsp90-assisted proteasomal pathway, interferes with the heterodimerization of Her3 with Her2/c-Met, and attenuates downstream Erk/Akt signaling, thereby inhibiting Her3-dependent cancer cell growth. TX2-121-1 can be used for the research of non-small cell lung cancer, ovarian cancer and Her3-driven breast cancer^{[1][2][3][4][5][6]}. In Vitro:TX2-121-1 (compound 2e) binds to purified Her3 with an IC₅₀ of 49 nM^[1].
TX2-121-1 (2 μM) acts as a selective binder for Her3 in live cells^[1].
TX2-121-1 (1-5 μM; 12 h) induces partial degradation of Her3 in PC9 GR4 cells^[1].
TX2-121-1 (0.5-2 μM; 12 h) reduces the phosphorylation levels of Erk and Akt, downstream effectors of Her3, in serum-starved PC9 GR4 cells stimulated with neuregulin^[1].
TX2-121-1 (1 μM; 6 h) reduces the heterodimerization of Her3 with Her2 and c-Met in PC9 GR4 cells^[1].
TX2-121-1 (3 h) potently binds to the purified human Her3 kinase domain with an IC₅₀ of 49.2 nM, and exhibits Her3-centered kinome selectivity, showing no direct inhibitory activity against EGFR or Her2 enzymes at concentrations below 10 μM^[3].
TX2-121-1 (1 μM; 6 h) inhibits the heterodimerization of Her3 with Her2 and c-Met in PC9 GR4 lung cancer cells, and exhibits stronger inhibitory activity against Her2/Her3 dimers^[3].
TX2-121-1 potently binds to purified Her3 protein, with an IC₅₀ value of 49.2 nM^[4].
TX2-121-1 (500 nM) covalently binds to and degrades endogenously expressed ErbB3 in ErbB3-dependent cell lines, thereby inhibiting downstream signal transduction and cell proliferation^[5].
TX2-121-1 inhibits HER3-dependent signaling pathways, induces partial degradation of HER3, and disrupts the heterodimerization of HER3 with HER2 and c-Met in cultured cells^[6].
TX2-121-1 inhibits the proliferation of PC9 GR4 cells, and its potency is approximately 7-fold that of the non-covalent control TX2-135-2^[1].
TX2-121-1 selectively induces PC9 GR4 cell death by enhancing the inhibition of Her3-dependent signaling, with an EC₅₀ of 0.87 μM^[2].
TX2-121-1-mediated intracellular Her3 degradation is enhanced upon combined treatment with the chaperone inhibitors 116-9e or Tanespimycin (17-AAG) (HY-10211)^[2].
TX2-121-1 (0.5-2 μM; 12 h) induces partial degradation of Her3 in starved PC9 GR4 lung cancer cells and inhibits NRG-stimulated phosphorylation of Erk and Akt^[3].
TX2-121-1 (administered consecutively for 3 days) inhibits the proliferation of PC9 GR4 lung cancer cells expressing wild-type Her3, with an EC₅₀ of 0.9 μM; in cells expressing the Her3^C721S mutant, the activity of this compound decreases (EC₅₀ = 5.5 μM), indicating that its targeting activity depends on covalent binding to Cys721^[3].
TX2-121-1 (administered for 3 consecutive days) selectively inhibits the proliferation of Her3-dependent cancer cell lines (PC9 GR4, HCC827 GR6, Ovcar8), with EC₅₀ values ranging from 0.8 to 1.4 μM^[3].
Degradation of Her3 in PC9 GR4 lung cancer cells induced by TX2-121-1 (0.5 μM) is enhanced by inhibition of Hsp70 or Hsp90, and is dependent on the proteasome^[3].
TX2-121-1 (2 μM; 12 h) induces partial degradation of Her3 in starved PC9 GR4 cells, thereby inhibiting the downstream Her2 and c-Met signaling pathways^[4].
TX2-121-1 inhibits the proliferation of Her3-dependent PC9 GR4, HCC827 GR6 and Ovcar8 cell lines, with EC₅₀ values ranging from 0.8 to 1.4 μM^[4].