2. PROTAC Metabolic Enzyme/Protease
  3. Molecular Glues E1/E2/E3 Enzyme
  4. XMU-MP-8

XMU-MP-8 (SKPer1) is a potent molecular glue degrader that targets the oncoprotein SKP2. XMU-MP-8 simultaneously binds to the F-box domain of SKP2 (Kd ≈ 36 μM) and the N-terminal TPR domain of the E3 ligase STUB1 (Kd ≈ 2.5 μM), forming a stable SKP2-SKPer1-STUB1 ternary complex (Kd ≈ 8.9 nM) that induces SKP2 ubiquitination and proteasomal degradation. XMU-MP-8 selectively eliminates SKP2-expressing cancer cells. XMU-MP-8 exhibits substantial tumour suppression with good safety profiles in vivo. XMU-MP-8 can be used for cancer research, such as non-small cell lung adenocarcinoma (NSCLC) and prostatic adenocarcinoma.

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XMU-MP-8

XMU-MP-8 Chemical Structure

CAS No. : 2271314-01-1

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XMU-MP-8 Related Antibodies

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Description

XMU-MP-8 (SKPer1) is a potent molecular glue degrader that targets the oncoprotein SKP2. XMU-MP-8 simultaneously binds to the F-box domain of SKP2 (Kd ≈ 36 μM) and the N-terminal TPR domain of the E3 ligase STUB1 (Kd ≈ 2.5 μM), forming a stable SKP2-SKPer1-STUB1 ternary complex (Kd ≈ 8.9 nM) that induces SKP2 ubiquitination and proteasomal degradation. XMU-MP-8 selectively eliminates SKP2-expressing cancer cells. XMU-MP-8 exhibits substantial tumour suppression with good safety profiles in vivo. XMU-MP-8 can be used for cancer research, such as non-small cell lung adenocarcinoma (NSCLC) and prostatic adenocarcinoma[1].

IC50 & Target[1]

SKP2

36 μM (Kd)

In Vitro

XMU-MP-8 (10 μM, 24 h) produces a cell survival phenotype specifically in the SKP2-F-C cell line, with no survival observed in other F-C cell lines, ruling out the possibility that it generally interferes with the activation of the F-C death protein[1].
XMU-MP-8 (1-10 μM, 0-24 h) triggers SKP2 ubiquitination and proteasomal degradation, significantly reducing its half-life and depleting endogenous SKP2 protein without affecting its mRNA levels[1].
XMU-MP-8 (72 h) inhibits proliferation of SKP2-high cell lines with IC50s of 3.7 μM (PC-3), 6.7 μM (A549), 3.7 μM (JHH-7), 6.2 μM (SW620), 4.5 μM (LoVo), 6.9 μM (RKO), 5.6 μM (Caco2) and 5.3 μM (HeLa)[1].
XMU-MP-8 (10 μM ,72 h) completely blocks proliferation and induces massive cell death of SKP2-high cell lines[1].
XMU-MP-8 (10 μM, 24 h) induces the degradation of SKP2 protein and the accumulation of p27 protein in SKP2-high cell lines (JHH-7 and PC-3), with no significant changes in SKP2-low cell lines (IMR-90 and MCF-10A)[1].
XMU-MP-8 (2.5-10 μM, 0-5 days) shows no significant effect on the growth of normal mouse intestine organoids and human peripheral blood mononuclear cells[1].
XMU-MP-8 (10 μM ,2.5 h) induces SKP2 degradation by recruiting the E3 ligase STUB1 to the F-box domain of SKP2, forming a ternary complex that enhances the SKP2-STUB1 interaction by 122-fold and ultimately leads to SKP2 ubiquitination and degradation[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

XMU-MP-8 Related Antibodies

Western Blot Analysis[1]

Cell Line: JHH-7 and HeLa cells
Concentration: 1, 2, 5, and 10 μM
Incubation Time: 0, 2, 4, 6, 8, 12 and 24 h
Result: Reduced SKP2 levels in JHH-7 and HeLa cells in a dose- and time-dependent manner.
Degraded SKP2 through the proteasome, but not the lysosome.
Induced ubiquitination of SKP2.
Significantly reduced the SKP2 half-life of SKP2 (from 10.8 h to 3.3 h in JHH-7 cells, and from 11.3 h to 6.2 h in HeLa cells).

Western Blot Analysis[1]

Cell Line: A549 and PC-3 cells and derived genetically modified lines.
Concentration: 5 and 10 μM
Incubation Time: 2.5 and 24 h
Result: Failed to degrade SKP2-F-C when three lysine residues (3K>R) in its F-box domain were mutated.
Failed to induce ubiquitination of the SKP2 3K>R mutant protein.
Was unable to exert its anti-proliferative effect in cells where endogenous SKP2 had been replaced with the degradation-resistant 3K>R mutant.
Failed to induce SKP2 ubiquitination and degradation in STUB1 knockout cells.
Re-gained its ability to degrade SKP2 following the reconstitution of sgRNA-resistant STUB1 in STUB1 knockout cells.
Still recruited the 3K>R mutant to STUB1, even though this mutant was resistant to degradation.
In Vivo

XMU-MP-8 (15 and 30 mg/kg, i.v., daily for 14 days) demonstrates potent antitumor efficacy in A549 and PC-3 xenograft mice models, mediated through SKP2 degradation[1].
XMU-MP-8 (30 mg/kg, i.v., daily for 14 days) shows no adverse effects in BALB/c nude mice[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: Male BALB/c nude mice (6 weeks old)[1]
Dosage: 30 mg/kg
Administration: i.v., daily for 14 days
Result: Exhibited no significant changes in body weight and liver function (ALT/AST levels).
Showed no histopathological damage in the heart, kidney, liver, lung, or spleen.
Animal Model: Male BALB/c nude mice (6 weeks old) subcutaneously injected with A549 or PC-3 cells[1]
Dosage: 15 and 30 mg/kg
Administration: i.v., daily for 14 days
Result: Completely ceased the growth of A549 tumors.
Caused a 95 % reduction in tumour growth in PC-3 xenograft model.
Caused depletion of SKP2 and an increase of p27 in the xenograft PC-3 tumour.
Molecular Weight

534.56

Formula

C26H21F3N8S
CAS No.
SMILES

CN1N=CC2=C(NCC3=CC=CN=C3)N=C(C4=CC=CC(NC(NC5=CC=CC(C(F)(F)F)=C5)=S)=C4)N=C21
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Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
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XMU-MP-8 Related Classifications

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Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

XMU-MP-82271314-01-1SKPer1SKPer 1SKPer-1Molecular GluesE1/E2/E3 EnzymeE1 activating enzymeE2 conjugating enzymeE3 ligating enzymeUbiquitin activating enzymeUbiquitin conjugating enzymeUbiquitin ligaseSKP2E3STUB1NSCLCadenocarcinomaA549PC-3SKP2-SKPer1-STUB1molecular glueInhibitorinhibitorinhibit

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