Ubiquitin

The ubiquitin-proteasome system (UPS) targets numerous cellular proteins for degradation. It is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a variety of basic cellular processes[1]. Degradation of a protein via the ubiquitin-proteasome pathway involves two discrete and successive steps: (1) tagging of the substrate by covalent attachment of multiple ubiquitin molecules to synthesize the polyubiquitin chain proteolytic signal and (2) degradation of the tagged protein by the 26S proteasome complex with release of free and reusable ubiquitin catalyzed by ubiquitin-recycling enzymes (DUBs)[2]. Conjugation of ubiquitin to the protein substrate proceeds via a three-step cascade mechanism. Initially, the ubiquitin-activating enzyme E1 activates ubiquitin in an ATP-requiring reaction resulting in a high-energy thiol ester intermediate. Subsequently, this intermediate is transferred to a member of the ubiquitin-carrier proteins family of enzymes, E2 (also known as a ubiquitin-conjugating enzyme [UBC]). Finally, from E2, the activated ubiquitin moiety is attached to the substrate that is specifically bound to an E3, a member of the ubiquitin-protein ligase family of proteins[3]. By successively adding additional activated ubiquitin moieties to internal Lys residues on the previously conjugated ubiquitin molecule, a polyubiquitin chain is synthesized. The degradation signal that is recognized by the 26S proteasome complex is made of a Lys48 polyubiquitin chain. In contrast, monoubiquitination or polyubiquitination with chains linked together via Lys63 serve as nonproteolytic signals in intracellular trafficking, DNA repair, activation of transcription and other signal transduction pathways[4].


[1] Drug discovery in the ubiquitin–proteasome system. G. Nalepa, M. Rolfe, J.W.Harper. Nature Reviews Drug Discovery2006, 5, 596-613.
[2] Mechanisms of Proteasome Inhibitor PS-341-induced G2-M-Phase Arrest and Apoptosis in Human Non-Small Cell Lung Cancer Cell Lines. Y Ling et al. Clin. Cancer Res. 2003, 9, 1145-1154.
[3] R.J. Deshaies, C.A.P. Joazeiro. RING Domain E3 Ubiquitin Ligases. Annu. Rev. Biochem. 2009, 78, 399-434.
[4] The Ubiquitin Proteasome System in Neurodegenerative Diseases: Sometimes the Chicken, Sometimes the Egg. A.Ciechanover, P. Brundin. Neuron 2003, 40, 427–446.

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Axon ID Name Description From price
2639 AMG 232 Potent, selective, and orally bioavailable MDM2-p53 inhibitor €120.00
3194 Apcin Inhibitor of APC/C-Cdc20 €110.00
2251 Apoptozole Inhibitor of ATPase activity of Hsc70 and Hsp70 €95.00
5051 Axon Ligands™ Cell signaling and Oncology compound library Axon Ligands™ Cell signaling and Oncology compound library Inquire
3898 BC-1215 Selective and reversible Fbxo3 inhibitor €99.00
3211 BC1618 Potent, orally bioavailable, and metabolically stable Fbxo48 inhibitor €120.00
3361 BI-3802 Highly potent and efficacious BCL6 degrader €130.00
1810 Bortezomib Inhibitor of 26S proteasome €80.00
3846 C25-140 First-in-class TRAF6–Ubc13 inhibitor €160.00
2645 CC-885 Cereblon (CRBN) modulator with potent anti-tumour activity €130.00
3763 CFT-7455 Orally active monofunctional degrader for IKZF1/3 Inquire
2935 COH000 First-in-class, highly specific, covalent allosteric inhibitor of SUMO E1 €175.00
2879 CP 31398 Stabilizer of p53 and inducer of apoptosis €100.00
1826 DBeQ Inhibitor of p97 ATPase €90.00
3292 dCeMM1 Glue degrader of RBM39 €110.00
3293 dCeMM2 Glue degrader of Cyclin K €100.00
3709 DKM 2-93 Selective inhibitor of UBA5 €70.00
3765 DS-3032 Orally available, potent and selective inhibitor of the p53-MDM2 interaction Inquire
1798 Eeyarestatin I Inhibitor of endoplasmic reticulum associated protein degradation (ERAD) €80.00
3613 EN219 Covalent RNF114 ligand €120.00
2348 GNE 7915 Potent, selective, metabolically stable, and brain-penetrable LRRK2 inhibitor €110.00
2181 GSK 2578215A Potent and highly selective LRRK2 inhibitor €125.00
2713 GSK 2982772 Specific inhibitor of RIP1 kinase €115.00
2608 GSK481 Potent inhibitor of RIP1 kinase and TNF induced inflammation €95.00
3732 HBX 41,108 Inhibitor of deubiquitinase USP7 €110.00
1643 HLI 373 HDM2 inhibitor €100.00
3064 HOIPIN 11a Selective, cell-permeable and covalent inhibitor of RBR E3 ubiquitin ligase HOIP €180.00
2972 HOIPIN-8 Potent linear ubiquitin chain assembly complex (LUBAC) inhibitor €130.00
3470 Homo-PROTAC cereblon degrader 1 Highly potent and efficient CRBN degrader; PROTAC €230.00
3426 IU1-47 Potent and selective inhibitor deubiquitinase USP14 €80.00

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