2. PROTAC Apoptosis
  3. PROTACs RIP kinase Apoptosis
  4. LD4172

LD4172 is a selective RIPK1 PROTAC degrader with a Ki of 4.8 nM. LD4172 induces RIPK1 protein degradation via ternary complex formation with RIPK1 and VHL E3 ligase, driving ubiquitination and proteasomal breakdown. LD4172 abrogates TNF-induced classical NF-κB signaling in TRAF2-deficient cells, impairing IκBα phosphorylation and degradation, and reducing IL-8 production. LD4172 induces apoptosis and immunogenic cell death in tumor cells, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy. LD4172 acts as a chemical probe for investigating RIPK1 scaffolding functions. LD4172 can be used for the research of melanoma, colon cancer.
(Pink: RIPK1 Target protein ligand; Blue: VHL ligand (HY-112078); Black: linker (HY-W012241)).

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LD4172

LD4172 Chemical Structure

CAS No. : 2782022-40-4

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Based on 1 publication(s) in Google Scholar

LD4172 Related Antibodies

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RIPK1 RIPK2 RIPK3

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Description

LD4172 is a selective RIPK1 PROTAC degrader with a Ki of 4.8 nM. LD4172 induces RIPK1 protein degradation via ternary complex formation with RIPK1 and VHL E3 ligase, driving ubiquitination and proteasomal breakdown. LD4172 abrogates TNF-induced classical NF-κB signaling in TRAF2-deficient cells, impairing IκBα phosphorylation and degradation, and reducing IL-8 production. LD4172 induces apoptosis and immunogenic cell death in tumor cells, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy. LD4172 acts as a chemical probe for investigating RIPK1 scaffolding functions. LD4172 can be used for the research of melanoma, colon cancer[1][2]. (Pink: RIPK1 Target protein ligand; Blue: VHL ligand (HY-112078); Black: linker (HY-W012241)).

IC50 & Target

hRIP1

4.8 nM (Ki)

VHL

 

In Vitro

LD4172 (1 μM; 24 h) efficiently degrades RIPK1 in HCT116-PIK3CAmut, HeLa-RIPK3, and HT29 cells, and abrogates TNF-induced classical NFκB signaling in TRAF2-deficient variants of these cell lines, while leaving signaling intact in parental cells[1].
LD4172 potently binds to recombinant human RIPK1 protein with a biochemical Ki of 4.8 nM[2].
LD4172 engages intracellular RIPK1 in HEK293T cells with an apparent Ki of 1.9 μM[2].
LD4172 (10-100 nM; 4 h with 30 min pre-incubation with MG132) dose-dependently forms a ternary complex with RIPK1 and VHL in HEK293T cells[2].
LD4172 (0.016-10 μM; 24 h) potently degrades RIPK1 in a panel of human and mouse cell lines, with DC50 values of 4-400 nM and >90% degradation at 1 μM for 24 h in Jurkat and B16F10 cells[2].
LD4172 (200 nM; 6 h) induces highly specific degradation of RIPK1 in MDA-MB-231 cells, with no detectable degradation of other proteins including off-target kinases of the warhead[2].
LD4172 (1 μM; 24 h, co-treated with 100 ng/mL TNF-α) inhibits TNF-α-induced NF-κB activity in B16F10 mouse melanoma cells[2].
LD4172 (1 μM; 72 h, co-treated with 100 ng/mL TNF-α where indicated) sensitizes B16F10 mouse melanoma cells to TNF-α-induced apoptosis and immunogenic cell death[2].

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

LD4172 Related Antibodies

Western Blot Analysis[1]

Cell Line: HCT116-PIK3CAmut, HeLa-RIPK3, HT29 cells, and their TRAF2-deficient variants
Concentration: 1 μM
Incubation Time: 24 h
Result: Reduced RIPK1 expression efficiently in all tested cell lines and their TRAF2-deficient variants. Left TNF-induced NFκB signaling (measured by IκBα phosphorylation/degradation and IL-8 production) largely unaffected in parental cells. Abrogated TNF-induced NFκB signaling practically in TRAF2-deficient cells.

Western Blot Analysis[2]

Cell Line: Jurkat, B16F10 cells
Concentration: 1 μM
Incubation Time: 0, 2, 4, 8, 12, 24, 48 h
Result: Induced >90% RIPK1 degradation within 2 h in Jurkat cells and 4 h in B16F10 cells. Initiated RIPK1 resynthesis 4 h post-washout, with resynthesis half-lives of ~48 h in Jurkat cells and ~24 h in B16F10 cells.

Apoptosis Analysis[2]

Cell Line: B16F10 mouse melanoma cells
Concentration: 1 μM (co-treated with 100 ng/mL TNF-α where indicated)
Incubation Time: 72 h
Result: Combined with TNF-α to induce significant apoptosis, evidenced by increased Annexin V/PI positivity, cleaved caspase 3/7 staining, PI uptake, and elevated levels of cleaved caspase-3, cleaved caspase-7, and cleaved PARP. Combined with TNF-α to trigger immunogenic cell death, marked by increased extracellular ATP, release of HMGB1, and downregulation of intracellular calreticulin.
Parmacokinetics
Species Dose Route T1/2 Cmax AUC Vd CL
Mice[2] 1 mg/kg i.v. 3.3 h 6.3 μM 0.7 μM·h 1100 mL/kg 19.8 mL/min/kg
Mice[2] 10 mg/kg i.p. 1.5 h 2.9 μM 2.7 μM·h / /
In Vivo

LD4172 (20 mg/kg; i.p.; twice daily) achieves tumor-selective RIPK1 degradation, induces immunogenic cell death, and synergizes with anti-PD1 to significantly reduce tumor weight, extend survival, and reshape the tumor immune microenvironment in female C57BL/6J mice bearing B16F10 melanoma[2].
LD4172 (20 mg/kg; i.p.; daily) synergizes with anti-PD1 to improve antitumor efficacy in female C57BL/6J mice bearing the MC38 colon carcinoma model[2].

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

Animal Model: C57BL/6J (female, 7 weeks old) injected with B16F10 cells[2]
Dosage: 20 mg/kg
Administration: i.p.; daily
Result: Induced a 60% reduction in RIPK1 levels in tumors; less than 50% RIPK1 degradation was observed in the spleen, and no significant degradation was seen in lymph nodes, PBMCs, lungs, or bone marrow.
Animal Model: C57BL/6J (female, 7 weeks old) injected with MC38 cells[2]
Dosage: 20 mg/kg
Administration: i.p.; daily
Result: Sensitized MC38 tumors to anti-PD1 therapy, enhancing the antitumor response relative to single-agent treatments.
Molecular Weight

1149.37

Formula

C61H75F3N10O7S
CAS No.
Appearance

Solid

Color

White to off-white

SMILES

O=C(CC1=CC=CC(OC(F)(F)F)=C1)N2CCC3=C2C=CC(C4=CN(C5=NC=NC(N)=C45)CCCNC(CCCCCCCCCCC(N[C@H](C(N6C[C@@H](C[C@H]6C(N[C@H](C7=CC=C(C=C7)C8=C(N=CS8)C)C)=O)O)=O)C(C)(C)C)=O)=O)=C3
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 : ≥ 100 mg/mL (87.00 mM; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

*"≥" means soluble, but saturation unknown.

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
1 mM 0.8700 mL 4.3502 mL 8.7004 mL
5 mM 0.1740 mL 0.8700 mL 1.7401 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 Dissolution Calculator
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Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
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Purity & Documentation

Purity: 98.32%

SDS (254 KB)

COA (250 KB) HNMR (276 KB) LCMS (89 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 0.8700 mL 4.3502 mL 8.7004 mL 21.7510 mL
5 mM 0.1740 mL 0.8700 mL 1.7401 mL 4.3502 mL
10 mM 0.0870 mL 0.4350 mL 0.8700 mL 2.1751 mL
15 mM 0.0580 mL 0.2900 mL 0.5800 mL 1.4501 mL
20 mM 0.0435 mL 0.2175 mL 0.4350 mL 1.0876 mL
25 mM 0.0348 mL 0.1740 mL 0.3480 mL 0.8700 mL
30 mM 0.0290 mL 0.1450 mL 0.2900 mL 0.7250 mL
40 mM 0.0218 mL 0.1088 mL 0.2175 mL 0.5438 mL
50 mM 0.0174 mL 0.0870 mL 0.1740 mL 0.4350 mL
60 mM 0.0145 mL 0.0725 mL 0.1450 mL 0.3625 mL
80 mM 0.0109 mL 0.0544 mL 0.1088 mL 0.2719 mL
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LD4172 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:

LD41722782022-40-4LD 4172LD-4172PROTACsRIP kinaseApoptosisReceptor-interacting protein kinasesRIPKTRAF2-deficient cellsanti-PD1 therapyRIPK1colon cancerVHL E3 ligasetumor-infiltrating lymphocyteIL-8NFκB signalingmelanomaIκBαInhibitorinhibitorinhibit

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