2. PROTAC Apoptosis
  3. PROTACs MDM-2/p53 Apoptosis
  4. Seldegamadlin

Seldegamadlin (KT-253) is a selective p53 stabilizer and a MDM2 PROTAC degrader (DC50 = 0.4 nM). Seldegamadlin inhibits the proliferation of cancer cell RS4;11 with an IC50 of 0.3 nM, arrests the cell cycle at G2/M phase, and induces apoptosis. Seldegamadlin upregulates p53 activity and overcomes the p53-MDM2 feedback loop. Seldegamadlin can be used for the study of hematologic and solid tumors, such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). (Pink: ligand for target protein MDM2 ligand 4 (HY-170452); Black: linker (HY-W001478); Blue: ligand for E3 ligase cereblon (HY-163927)).

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Seldegamadlin

Seldegamadlin Chemical Structure

CAS No. : 2713618-08-5

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Based on 1 publication(s) in Google Scholar

Seldegamadlin Related Antibodies

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von Hippel-Lindau (VHL) Cereblon MDM2 cIAP1

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Description

Seldegamadlin (KT-253) is a selective p53 stabilizer and a MDM2 PROTAC degrader (DC50 = 0.4 nM). Seldegamadlin inhibits the proliferation of cancer cell RS4;11 with an IC50 of 0.3 nM, arrests the cell cycle at G2/M phase, and induces apoptosis. Seldegamadlin upregulates p53 activity and overcomes the p53-MDM2 feedback loop. Seldegamadlin can be used for the study of hematologic and solid tumors, such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). (Pink: ligand for target protein MDM2 ligand 4 (HY-170452); Black: linker (HY-W001478); Blue: ligand for E3 ligase cereblon (HY-163927))[1][2][3][4].

IC50 & Target[1][2][3]

Cereblon

 

In Vitro

KT-253 degrades MDM2 with subnanomolar potency at concentrations of 0.01 nmol/L, 0.1 nmol/L, 1 Seldegamadlin (KT-253) inhibits cell viability of RS4;11 ALL cells with an IC50 of 0.3 nM. The strong growth inhibition by KT-253 Is driven by the recruitment of both CRBN and MDM2[3].
Seldegamadlin (1.8 nM; 2-4 h) inhibits MDM2 protein expression in RS4;11 ALL cells[3].
Seldegamadlin (20 nM; 2-8 h) induces selective and temporal upregulation of p53 and its downstream targets in RS4;11 ALL cells[3].
Brief exposure to Seldegamadlin (1-1000 nM; 4 h) is sufficient to trigger apoptosis in RS4;11 ALL cells[3].
Seldegamadlin (0.01-10000 nM; 8 h) shows potent induction of p53 transcriptional gene targets, including MDM2, GDF15, CDKN1A, GADD45A, TNFRSF10B, FAS, and BBC3[3].
Seldegamadlin (1-1000 nM; 4 h) resultes in a significantly lower percentage of cells in S-phase in RS4;11 and MV4;11 cells[3].
Seldegamadlin (1-10,000 nM; 48-96 h) is active in various solid tumor cell lines including neuroblastoma, rhabdoid, eye, bile duct, colorectal, liposarcoma, gastric sarcoma, bone, breast, lung, prostate, liver, brain, kidney, thyroid, bladder, skin, ovarian, cervical, endometrial/uterine, head and neck, non-Cancerous, pancreatic[4].

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

Seldegamadlin Related Antibodies

Western Blot Analysis[3]

Cell Line: RS4;11 cells
Concentration: 1.8 nM
Incubation Time: 2 h and 4 h
Result: Led to potent and sustained MDM2 degradation to undetectable levels.

RT-PCR[3]

Cell Line: RS4;11 cells
Concentration: 20 nM
Incubation Time: 2 h, 4 h and 6 h
Result: Showed the upregulation of p53, p21 and PHLDA3.

Apoptosis Analysis[3]

Cell Line: RS4;11 cells
Concentration: 1 nM, 10 nM, 100 nM, 1000 nM
Incubation Time: 4 h
Result: The 4-hour treatment was sufficient to induce apoptosis over a 48-hour time frame.

Cell Cycle Analysis[3]

Cell Line: RS4;11 and MV4;11 cells
Concentration: 1 nM, 10 nM, 100 nM, 1000 nM
Incubation Time: 4 h
Result: Resulted in a significantly lower percentage of cells in S-phase.
In Vivo

Seldegamadlin (KT-253) (1 mg/kg-10 mg/kg; IV) achieves sustained tumor regression in RS4;11 (ALL) and MV-4-11 (AML) xenograft mice models[1].
Seldegamadlin (1-3 mg/kg; IV; once) triggeres rapid apoptosis and sustaines tumor regression in RS4;11 tumor–bearing mice[3].
In the MOLM-13 subcutaneous xenograft model, the combination of Seldegamadlin (3 mg/kg; intravenous injection; single dose) and Venetoclax (HY-15531) overcame Venetoclax resistance[3].
Seldegamadlin (3-10 mg/kg; IV; Q3W) inhibits tumor growth in multiple PDX solid tumor models, achieving complete responses[4].

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

Animal Model: Immuno-compromised host strain mice were subcutaneous with RS4;11 (ALL) cell lines[1]
Dosage: 1 mg/kg, 3 mg/kg, 10 mg/kg
Administration: IV; once
Result: Achieved sustained tumor regression in RS4;11 xenograft model.
Led to rapid increase in p53, p21 and PUMA (1 mg/kg).
Animal Model: Female Balb/c nude mice were subcutaneously MV4;11 cells in the hind flank of the animals.[3]
Dosage: 1 mg/kg, 3 mg/kg
Administration: IV; once
Result: Induced tumor regressions.
Demonstrated robust degradation of MDM2.
Showed an upregulation of proteomic biomarkers p53, p21, and PHLDA3.
Revealed robust upregulation of p53 and induction of apoptosis, as indicated by cleaved caspase-3 (CC-3) staining.
Led to robust activation of mRNA markers of both the intrinsic (BBC3) and extrinsic (TNFRSF10B and FAS) apoptotic pathways.
Animal Model: Twenty-fourpediatric patient-derived xenograft (PDX) models (Ewing sarcoma, rhabdomyosarcoma, rhabdoid tumor,Wilms tumor, hepatoblastoma, and neuroblastoma, breast, lung,colorectal, gastric, melanoma) [4]
Dosage: 3 mg/kg, 10 mg/kg
Administration: IV; Q3W; total 3 dose
Result: Inhibited tumor growth in pediatric solid tumor models, achieving complete responses in 9 out of 24 models.
Animal Model: Immuno-compromised host strain mice were subcutaneous with MV-4-11 (AML) cell lines[1]
Dosage: 3 mg/kg
Administration: IV; once every 3 weeks
Result: Achieved sustained tumor regression in MV-4-11 xenograft model.
Led to rapid increase in GDF15, p21 and PUMA.
Clinical Trial
Molecular Weight

912.87

Formula

C48H52Cl2FN7O6
CAS No.
Appearance

Solid

Color

White to off-white

SMILES

ClC1=CC2=C([C@]3(C4(CCCCC4)N[C@@H](C(N[C@H]5CC[C@H](C(N6CCC(C7=CC=C8C(N(C)C(N8C9CCC(NC9=O)=O)=O)=C7)CC6)=O)CC5)=O)[C@@H]3C%10=C(F)C(Cl)=CC=C%10)C(N2)=O)C=C1
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

4°C, protect from light

*In solvent : -80°C, 6 months; -20°C, 1 month (protect from light)

Solvent & Solubility
In Vitro: 

DMSO : 95 mg/mL (104.07 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 1.0954 mL 5.4772 mL 10.9545 mL
5 mM 0.2191 mL 1.0954 mL 2.1909 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 (protect from light). 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
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 (protect from light). 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 1.0954 mL 5.4772 mL 10.9545 mL 27.3862 mL
5 mM 0.2191 mL 1.0954 mL 2.1909 mL 5.4772 mL
10 mM 0.1095 mL 0.5477 mL 1.0954 mL 2.7386 mL
15 mM 0.0730 mL 0.3651 mL 0.7303 mL 1.8257 mL
20 mM 0.0548 mL 0.2739 mL 0.5477 mL 1.3693 mL
25 mM 0.0438 mL 0.2191 mL 0.4382 mL 1.0954 mL
30 mM 0.0365 mL 0.1826 mL 0.3651 mL 0.9129 mL
40 mM 0.0274 mL 0.1369 mL 0.2739 mL 0.6847 mL
50 mM 0.0219 mL 0.1095 mL 0.2191 mL 0.5477 mL
60 mM 0.0183 mL 0.0913 mL 0.1826 mL 0.4564 mL
80 mM 0.0137 mL 0.0685 mL 0.1369 mL 0.3423 mL
100 mM 0.0110 mL 0.0548 mL 0.1095 mL 0.2739 mL
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Seldegamadlin 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:

Seldegamadlin2713618-08-5KT-253KT253KT 253PROTACsMDM-2/p53ApoptosisUveal melanomabiological activitypotencyxenograft modelAMLsmall molecule inhibitorssolid tumorstumor cell killingp53 stabilizationwildtype p53 tumorsprotein degradationapoptosisMDM2hematologic tumorsautoregulatory feedback loopSMItumor regressionMDM2 degraderp53venetoclax resistancetumor suppressionInhibitorinhibitorinhibit

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