Basic Information
Remarks
Chemical Identifiers
Basic Properties
Lipinski RO5
Hydrophobic Tag Properties
Mechanism of Action
POI (Protein of Interest)
Amino Acid Sequence
3D Structure (/structures/AF-P21860-F1-model_v6.cif)
Function
Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins. Binds to neuregulin-1 (NRG1) and is activated by it; ligand-binding increases phosphorylation on tyrosine residues and promotes its association with the p85 subunit of phosphatidylinositol 3-kinase. May also be activated by CSPG5. Involved in the regulation of myeloid cell differentiation.
Degradation Pathway
Mechanism
In an ATP-dependent manner, the ubiquitin-activating enzyme (E1) activates ubiquitin (Ub) and conjugates it to a ubiquitin-conjugating enzyme (E2). E3 ligase subsequently catalyzes the transfer of Ub to the target protein, leading to the formation of a polyubiquitin chain that completes the ubiquitination mark. The 19S regulatory particle of the 26S proteasome recognizes this ubiquitination signal and, after deubiquitination, mediates the ATP-dependent delivery of the substrate into the 20S proteasome for degradation.
Description
(a) Proteasome degradation pathway inhibitors block TX2-121-1 mediated effects while Hsp70 and Hsp90 inhibitors potentiate them. The Hsp90 inhibitor 17-AAG and the Hsp70 inhibitor 116-9e decrease detectable levels of Her3 protein in PC9 GR4 cells while the proteasome inhibitor MG132 protects Her3 from TX2-121-1 induced degradation, suggesting that the proteasome plays a central role in the degradation mechanism. (b) Cartoon for adamantane mediated degradation of Her3. Bulky hydrophobic chemical moieties are directed in cells to the proteasome degradation pathway. By tethering these substituents to Her3 using covalent chemistry, Her3 is also directed to the proteasome.
Activity Data
Description
A series of compounds possessing various linkers connecting TX1-85-1 with an adamantane moiety were synthesized and confirmed to bind potently with Her3, identifying a representative molecule (TX2-121-1) (6) demonstrating an IC 50 of 49.2 nM in the protein based binding assay
Description
We performed cell proliferation assays against PC9 GR4 cells expressing either wild-type or C721S mutant Her3 with TX1-85-1 and TX2-121-1 and their corresponding propylamide controls (TX1-85-3 (9) and TX2-135-2) in order to investigate the importance of the electrophilic acrylamide and the adamantane moiety. These experiments demonstrate a 6 fold rightward shift in EC 50 for C721S Her3 (EC 50 = 5.5 μM for PC9 GR4 Her3 C721S) versus wild-type Her 3 expressing cells (EC 50 =0.9 μM for PC9 GR4 WT Her3) only for TX2-121-1 which possesses both an electrophilic warhead and an adamantane moiety and the downstream signaling western blot is consistent with the antiproliferation result
Description
We performed cell proliferation assays against PC9 GR4 cells expressing either wild-type or C721S mutant Her3 with TX1-85-1 and TX2-121-1 and their corresponding propylamide controls (TX1-85-3 (9) and TX2-135-2) in order to investigate the importance of the electrophilic acrylamide and the adamantane moiety. These experiments demonstrate a 6 fold rightward shift in EC 50 for C721S Her3 (EC 50 = 5.5 μM for PC9 GR4 Her3 C721S) versus wild-type Her 3 expressing cells (EC 50 =0.9 μM for PC9 GR4 WT Her3) only for TX2-121-1 which possesses both an electrophilic warhead and an adamantane moiety and the downstream signaling western blot is consistent with the antiproliferation result
Disease Information
| Disease | ICD-11 | Source |
|---|---|---|
| lung adenocarcinoma | 2C25.0 | Cell Line Origin |
| Lethal congenital contracture syndrome 2 (LCCS2) | LD26.4Y | Gene-Disease Association |
| Hirschsprung disease | LB16.1 | Gene-Disease Association |
| Malignant neoplasms of bladder | 2C94 | Gene-Disease Association |
| Breast Cancer | 2C6Z | Gene-Disease Association |
| Distal arthrogryposis | LD26.4Y | Gene-Disease Association |
| Congenital Myasthenic Syndrome | 8C61 | Gene-Disease Association |
| Ovarian Cancer | 2C73.Z | Gene-Disease Association |