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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Solid + Solvent (Highly Recommended)
10 mM * 1 mL in DMSO
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Based on 1 publication(s) in Google Scholar

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.
Appearance

Solid

Color

White to off-white

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
Shipping

Room temperature in continental US; may vary elsewhere.
Storage
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 6 months
-20°C 1 month
Solvent & Solubility
In Vitro: 

DMSO : 116.67 mg/mL (218.25 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
1 mM 1.8707 mL 9.3535 mL 18.7070 mL
5 mM 0.3741 mL 1.8707 mL 3.7414 mL
View the Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

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Purity & Documentation

Purity: 99.23%

SDS (393 KB)

COA (249 KB) HNMR (291 KB) RP-HPLC (258 KB) MS (228 KB)

Handling Instructions (2659 KB)
References

Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 1.8707 mL 9.3535 mL 18.7070 mL 46.7674 mL
5 mM 0.3741 mL 1.8707 mL 3.7414 mL 9.3535 mL
10 mM 0.1871 mL 0.9353 mL 1.8707 mL 4.6767 mL
15 mM 0.1247 mL 0.6236 mL 1.2471 mL 3.1178 mL
20 mM 0.0935 mL 0.4677 mL 0.9353 mL 2.3384 mL
25 mM 0.0748 mL 0.3741 mL 0.7483 mL 1.8707 mL
30 mM 0.0624 mL 0.3118 mL 0.6236 mL 1.5589 mL
40 mM 0.0468 mL 0.2338 mL 0.4677 mL 1.1692 mL
50 mM 0.0374 mL 0.1871 mL 0.3741 mL 0.9353 mL
60 mM 0.0312 mL 0.1559 mL 0.3118 mL 0.7795 mL
80 mM 0.0234 mL 0.1169 mL 0.2338 mL 0.5846 mL
100 mM 0.0187 mL 0.0935 mL 0.1871 mL 0.4677 mL
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XMU-MP-8 Related Classifications

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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