2. PROTAC Metabolic Enzyme/Protease Apoptosis Immunology/Inflammation NF-κB MAPK/ERK Pathway
  3. PROTACs Ser/Thr Kinase TNF Receptor Toll-like Receptor (TLR) NF-κB p38 MAPK
  4. R1-ICR-5

R1-ICR-5 is a highly selective RIPK1 PROTAC degrader. Mediated by VHL, R1-ICR-5 induces the degradation of RIPK1, which in turn dysregulates the TNFR1 and TLR3/4 signaling hubs, enhances the signaling outputs of NF-κB, MAPK and IFN, and simultaneously promotes RIPK3 activation and necroptosis (necroptosis). R1-ICR-5 can be used in the research of triple-negative breast cancer and skin inflammation.
(Pink: RIPK1 ligand (HY-128348); Blue: VHL ligand (HY-125845); Black: linker (HY-W012241)).

For research use only. We do not sell to patients.

R1-ICR-5

R1-ICR-5 Chemical Structure

CAS No. : 3070346-91-4

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Based on 1 publication(s) in Google Scholar

R1-ICR-5 Related Antibodies

Top Publications Citing Use of Products

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p38 MAPK Akt1 p38α p38β MAPK13 p38δ p38γ

  • Biological Activity

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Description

R1-ICR-5 is a highly selective RIPK1 PROTAC degrader. Mediated by VHL, R1-ICR-5 induces the degradation of RIPK1, which in turn dysregulates the TNFR1 and TLR3/4 signaling hubs, enhances the signaling outputs of NF-κB, MAPK and IFN, and simultaneously promotes RIPK3 activation and necroptosis (necroptosis). R1-ICR-5 can be used in the research of triple-negative breast cancer and skin inflammation[1]. (Pink: RIPK1 ligand (HY-128348); Blue: VHL ligand (HY-125845); Black: linker (HY-W012241)).

In Vitro

R1-ICR-5 (1 μM; 2-24 h) induces time-dependent, VHL- and proteasome-dependent degradation of RIPK1 in mouse bone marrow-derived macrophages (BMDMs) without off-target effects on related kinases[1].
R1-ICR-5 (20 h) potently degrades endogenous RIPK1 protein in human HT1080 and HT29 cells, as well as mouse EMT6 and L929 cells[1].
R1-ICR-5 (1 μM; 24 h) reduces the resynthesis rate of RIPK1 in mouse Mlkl-/- BMDMs, and after washout following initial treatment with 1 μM R1-ICR-5, its protein level requires more than 72 h to recover to the pre-treatment level[1].
R1-ICR-5 (1 μM; 4 h) enhances the expression of TNF-induced NF-κB target genes Tnf, A20 and Sod2 in mouse BMDMs[1].
R1-ICR-5 (1 μM; 4 h) enhances the expression of TLR3-mediated NF-κB and IFN target genes in mouse BMDMs[1].
R1-ICR-5 (1 μM; 18 h) sensitizes human HT1080 cells to TNF-induced necroptosis[1].
R1-ICR-5 (1 μM; 5 h) sensitizes mouse BMDMs to TNF-induced necroptosis[1].
R1-ICR-5 (1 μM; 24 h) induces autocrine TNF-mediated necroptosis in mouse BMDMs, a process dependent on the TNFR1 signaling pathway and MK2-mediated TNF biosynthesis[1].
R1-ICR-5 (1 μM; 24 h) enhances the sensitivity of murine EO771 triple-negative breast cancer (TNBC) cells to radiation-induced necroptosis[1].

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

R1-ICR-5 Related Antibodies

Western Blot Analysis[1]

Cell Line: mouse bone marrow-derived macrophages (BMDMs)
Concentration: 1 μM (R1-ICR-5); 1 μM VH298 (VHL inhibitor, pre-incubation); 100 nM bortezomib (proteasome inhibitor, pre-incubation)
Incubation Time: 2 h, 4 h, 6 h, 12 h, 24 h (R1-ICR-5 treatment); 1 h (VH298/bortezomib pre-incubation, followed by R1-ICR-5 treatment)
Result: Caused RIPK1 degradation as early as 2 h, nearly complete by 6 h, and sustained through 24 h.
Blocked RIPK1 degradation when cells were pre-treated with VH298 or bortezomib.
Did not cause significant changes in protein levels of related kinases RIPK2, RIPK3, BRAF, or TrkA.

Western Blot Analysis[1]

Cell Line: mouse Mlkl-/- bone marrow-derived macrophages (BMDMs)
Concentration: 1 μM
Incubation Time: 24 h (initial treatment); 24 h, 48 h, 72 h (post-washout harvesting)
Result: Kept RIPK1 protein levels suppressed at 24 h post-washout, with levels beginning to recover by 48 h but not returning to pre-treatment levels even at 72 h post-washout.

Real Time qPCR[1]

Cell Line: mouse bone marrow-derived macrophages (BMDMs)
Concentration: 1 μM (R1-ICR-5 pre-incubation)
Incubation Time: 4 h (R1-ICR-5 pre-incubation); 2 h, 4 h, 6 h (subsequent TNF treatment)
Result: Accentuated TNF-induced upregulation of NF-κB target genes Tnf, A20, and Sod2, with significant increases in fold induction compared to DMSO controls (p<0.0001 for Tnf at 4 h, 6 h; p<0.001 for A20 at 6 h; p<0.0001 for Sod2 at 4 h, 6 h).

Real Time qPCR[1]

Cell Line: mouse bone marrow-derived macrophages (BMDMs)
Concentration: 1 μM (R1-ICR-5 pre-incubation)
Incubation Time: 4 h (R1-ICR-5 pre-incubation); unspecified (subsequent Poly(I:C) stimulation)
Result: Significantly enhanced Poly(I:C)-induced expression of NF-κB target genes Tnf, Il6, Ccl2 and IFN target genes Cxcl10, Cxcl9, Ifnb, with fold inductions significantly higher than DMSO controls (p<0.0001 for all genes).
In Vivo

Combination of R1-ICR-5 (40 µg per dose; intratumoral injection; 3 doses total) with 8 Gy radiotherapy enhances anti-tumor immunity, prolongs median survival to 35 days, induces durable tumor regression, and generates protective anti-tumor immune memory in a mouse orthotopic triple-negative breast cancer model[1].
Combination treatment with R1-ICR-5 (40 µg per dose; intratumoral injection; 3 doses total), 4 Gy radiotherapy, and anti-CTLA-4 immune checkpoint blockade induces near-complete tumor regression and significantly prolongs survival in a mouse orthotopic triple-negative breast cancer model[1].
When used in combination with anti-PD-1 immune checkpoint blockade therapy, R1-ICR-5 (40 µg per dose; intratumoral injection; 4 doses total) slows tumor growth, increases the response rate to 60%, and extends the median survival time to 36.5 days in a mouse orthotopic triple-negative breast cancer model[1].
R1-ICR-5 (10 mM; subcutaneous injection; single administration) blocks RIPK1-dependent skin inflammation and tissue damage induced by combined treatment with SMAC mimetic and pan-caspase inhibitor in mice[1].
R1-ICR-5 (10 mM; subcutaneous injection; single administration) completely inhibits TBK1 inhibition- and TNF-mediated skin inflammation and tissue damage in mice[1].

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

Animal Model: C57BL/6J (female, 5-6 weeks old, orthotopic EO771 mammary fat pad tumor model)[1]
Dosage: 40 µg per injection
Administration: intra-tumoral; 3 doses on days 1, 4, 7 post-radiotherapy
Result: Extended median survival to 35 days, compared to 24 days with radiotherapy alone.
Achieved complete tumor regression in 3 out of 10 treated mice, with 2 remaining tumor-free long-term.
Showed complete or partial responses in 50% of treated mice, versus minimal responses with radiotherapy alone.
Increased TNF+IFNγ+ immune cells (CD45+) infiltrating tumors, with elevated counts of TNF+IFNγ+ CD8+ T cells, CD4+ conventional T cells, γδ T cells, NK cells, and NK-T cells per gram of tumor tissue.
Rendered cured mice fully resistant to tumor re-challenge, with 0 out of 2 mice developing new tumors, compared to 7 out of 7 naïve mice.\nStrongly inhibited tumor growth, with 9 out of 10 mice responding to therapy and 8 achieving complete, long-term tumor regression.
Significantly extended survival, with a median survival that was not reached, compared to a median survival of 70.5 days with radiotherapy + anti-CTLA-4 alone.
Animal Model: C57BL/6J (female, 5-6 weeks old, orthotopic EO771 mammary fat pad tumor model)[1]
Dosage: 40 µg per injection
Administration: intra-tumoral; 4 doses on days 2, 4, 6, and 8
Result: Slowed tumor growth kinetics (measured by area under the tumor growth curve) and extended median survival to 36.5 days, compared to 28.5 days with anti-PD-1 alone.
Showed complete or partial responses in 60% of treated mice, with 3 out of 10 mice achieving complete, long-term tumor regression.
Animal Model: C57BL/6 (RIPK1-dependent skin inflammation model)[1]
Dosage: 10 mM
Administration: subcutaneous; single co-injection
Result: Reduced histopathological lesion severity, with a mean Histological Multivariant Lesion Score (HLS) of 55 (range 30-70), compared to a mean HLS of 214 (range 175-257) in mice treated with ASTX660 + emricasan alone.
Prevented deep epidermal ulceration, dermal fibrosis, and cellular necrosis induced by ASTX660 + emricasan.
Animal Model: C57BL/6 (TBK1 inhibition-induced skin inflammation model)[1]
Dosage: 10 mM
Administration: subcutaneous; single co-injection
Result: Completely protected mice from deep skin ulceration and tissue injury induced by TBK1 inhibition + TNF treatment.
Molecular Weight

1007.31

Formula

C54H70N8O7S2
CAS No.
Appearance

Solid

Color

Off-white to light yellow

SMILES

O=C(OC1CCCCC1)NC2=CC(C3=CC=C4N=C(NC(CCCCCCCCCCC(N[C@@H](C(C)(C)C)C(N5[C@H](C(NCC6=CC=C(C7=C(C)N=CS7)C=C6)=O)C[C@@H](O)C5)=O)=O)=O)SC4=C3)=CN=C2C
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Room temperature in continental US; may vary elsewhere.
Storage
Powder -20°C 3 years
In solvent -80°C 6 months
-20°C 1 month
Solvent & Solubility
In Vitro: 

DMSO : 100 mg/mL (99.27 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 0.9927 mL 4.9637 mL 9.9274 mL
5 mM 0.1985 mL 0.9927 mL 1.9855 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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In Vivo:

Select the appropriate dissolution method based on your experimental animal and administration route.

For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day.
The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

  • Protocol 1

    Add each solvent one by one:  10% DMSO    90% Corn Oil

    Solubility: ≥ 2.5 mg/mL (2.48 mM); Clear solution

    This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown). If the continuous dosing period exceeds half a month, please choose this protocol carefully.

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL Corn oil, and mix evenly.

In Vivo Dissolution Calculator
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Method for preparing stock solution: mg drug dissolved in μL  DMSO (Stock solution concentration: mg/mL).
The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
Method for preparing in vivo working solution for animal experiments: Take μL DMSO stock solution, add μL . μL , mix evenly, next add μL Tween 80, mix evenly, then add μL Saline.
 If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Purity & Documentation
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 0.9927 mL 4.9637 mL 9.9274 mL 24.8186 mL
5 mM 0.1985 mL 0.9927 mL 1.9855 mL 4.9637 mL
10 mM 0.0993 mL 0.4964 mL 0.9927 mL 2.4819 mL
15 mM 0.0662 mL 0.3309 mL 0.6618 mL 1.6546 mL
20 mM 0.0496 mL 0.2482 mL 0.4964 mL 1.2409 mL
25 mM 0.0397 mL 0.1985 mL 0.3971 mL 0.9927 mL
30 mM 0.0331 mL 0.1655 mL 0.3309 mL 0.8273 mL
40 mM 0.0248 mL 0.1241 mL 0.2482 mL 0.6205 mL
50 mM 0.0199 mL 0.0993 mL 0.1985 mL 0.4964 mL
60 mM 0.0165 mL 0.0827 mL 0.1655 mL 0.4136 mL
80 mM 0.0124 mL 0.0620 mL 0.1241 mL 0.3102 mL
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R1-ICR-5 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:

R1-ICR-53070346-91-4PROTACsSer/Thr KinaseTNF ReceptorToll-like Receptor (TLR)NF-κBp38 MAPKProtein Serine-Threonine KinaseTumor Necrosis Factor ReceptorTNFRNuclear factor-κBNuclear factor-kappaBRIPK1EMT6 cellsHT29 cellsU937 cellsmouse BMDMsVHLEO771 TNBC cellstriple negative breast cancerL929 cellsHT1080 cellsInhibitorinhibitorinhibit

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