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-J7MA22-F1-model_v6.cif)
Function
Essential for the formation and stability of microtubules . Required for the organization of the mitotic spindle and for the proper attachment of kinetochores to MTs. Promotes the recruitment of NUDC to the mitotic spindle for mitotic progression.
Degradation Pathway
Mechanism
The ubiquitin-proteasome pathway (UPP) constitutes the principal pathway for protein degradation in eukaryotic cells, mediating the breakdown of target proteins through ubiquitin tagging and subsequent proteasomal degradation. 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
To further elucidate the degradation mechanism, we investigated the involvement of protein degradation pathways. The proteasome inhibitor MG-132 markedly impaired H7-induced ALK degradation, suggesting that the proteasome plays a crucial role in this process (Fig. 6B). HyT promotes protein degradation by mimicking the characteristics of mis folded proteins, thereby triggering recognition and clearance by the cellular quality control machinery [31]. Therefore, we performed co- immunoprecipitation (co-IP) experiments to investigate whether Hsp70 is involved in the action. Co-IP analysis revealed increased binding between ALK and Hsp70, as well as ubiquitin after treatment with H7 for 24 h, suggesting that the engagement of Hsp70 and ubiquitin is essential for the H7-induced degradation of ALK (Fig. 6C). These results collectively indicated that the ubiquitin-proteasome system (UPS), with Hsp70 participation, is responsible for the ALK degradation induced by H7.
Activity Data
Description
Since compound H7 demonstrated superior degradation efficiency against EML4-ALK, H3122 cells were selected for further studies. Compound H7 exhibited a concentration-dependent ability to degrade EML4-ALK in H3122 cells, with complete degradation observed and a DC50 of 0.13 ±0.01 μM
Description
Compound H7 exhibited superior anti-proliferation activity in H3122 cells, with IC 50 of 0.23 ± 0.03 μM.
Disease Information
| Disease | ICD-11 | Source |
|---|---|---|
| lung adenocarcinoma | 2C25.0 | Cell Line Origin |
| Hemimegalencephaly | LA05.1 | Gene-Disease Association |
| Familial benign macrocephaly | LB70.3 | Gene-Disease Association |
| Overgrowth Syndrome | LD2C | Gene-Disease Association |
| Hydrocephalus | 8D64.Z | Gene-Disease Association |