| Size | Price | Stock | Qty |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| Other Sizes |
Purity: =99.0%
| Targets |
Sulanemadlin targets both MDM2 (murine double minute 2) and MDMX (also known as MDM4). It binds to the p53-binding pockets of MDM2 and MDMX with high affinity, with a dissociation constant (Kd) of 10.9 nM for MDM2 and 57 nM for MDMX. The compound disrupts the p53-MDM2 and p53-MDMX protein-protein interactions, thereby reactivating p53's tumor suppressor function in TP53 wild-type cancer cells.
Sulanemadlin targets the MDM2 and MDMX proteins, which are the primary negative regulators of the tumor suppressor p53. By binding to both MDM2 and MDMX, it prevents them from binding to p53, thereby stabilizing and activating p53. This leads to the transcription of p53 target genes that induce cell cycle arrest and apoptosis. |
|---|---|
| ln Vitro |
Sulanemadlin demonstrates potent antiproliferative activity against TP53 wild-type cancer cell lines, including AML, breast cancer, and T-cell lymphoma models. Treatment with ALRN-6924 (0-10 μM for 24 hours) stabilizes p53 and upregulates its downstream target genes including p21 (CDKN1A), MDM2, BAX, PUMA, and GADD45a in a dose-dependent manner. It induces G1 and G2/M cell cycle arrest and apoptosis via caspase-3/7 activation. ALRN-6924 also disrupts functional clonogenic and serial replating capacity of leukemia stem cell-enriched populations, showing superiority over MDM2-only inhibitors like RG7388. In CD34+ human bone marrow cells, ALRN-6924 induces reversible, dose-dependent cell cycle arrest and protects cells from topotecan-induced DNA damage.
In vitro, sulanemadlin is a potent inhibitor of the p53-MDM2 and p53-MDMX interactions. It stabilizes p53 and induces apoptosis in cancer cell lines with wild-type p53. |
| ln Vivo |
In mouse xenograft models, Sulanemadlin (5-20 mg/kg, intravenous) demonstrates significant antitumor activity across multiple TP53 wild-type tumor types. In AML xenograft models, ALRN-6924 markedly improves survival, with 50% of mice remaining in long-term remission without signs of disease after 150 days. In T-cell lymphoma patient-derived xenograft models, ALRN-6924 shows superior in vivo activity compared to the standard-of-care agent romidepsin. In a Phase I clinical trial, ALRN-6924 demonstrated a disease control rate of 59% (24/41 evaluable patients) with two confirmed complete responses and two partial responses. Notably, one patient with TP53 wild-type angioimmunoblastic T-cell lymphoma achieved a complete remission, and six patients were treated for over one year.
In vivo, sulanemadlin is being investigated in clinical trials for the treatment of various cancers. |
| Enzyme Assay |
Binding kinetics of ALRN-6924 were measured using competitive fluorescence polarization binding assays. A fluorescently labeled linear peptide (ALRN-3618, 5-FAM-β-alanine-pDI) was used as a binding probe, which bound to purified MDM2 (Kd = 33.6 nM) and MDMX (Kd = 83 nM). ALRN-6924 displaced ALRN-3618 from its EC80 binding site on both MDM2 and MDMX, demonstrating that they bind to the same p53-binding pocket. Surface plasmon resonance (Biacore) studies using immobilized MDM2- and MDMX-coated surfaces confirmed ALRN-6924 binding with wash-off half-lives of 85 minutes for MDM2 and 5 minutes for MDMX. The active metabolite ALRN-8714 was also assessed in pharmacokinetic studies using validated liquid chromatography-tandem mass spectrometry methods.
The binding of sulanemadlin to MDM2 and MDMX is assessed using biochemical assays such as SPR or TR-FRET. |
| Cell Assay |
For cell proliferation assays, TP53 wild-type and mutant AML, breast cancer, and T-cell lymphoma cell lines were seeded in 96-well plates and treated with serial dilutions of ALRN-6924 for 72 hours. Cell viability was measured using trypan blue exclusion or MTT assays. For Western blotting, cells were treated with ALRN-6924 (0-10 μM) for 4-24 hours, and protein lysates were analyzed for p53, p21, MDM2, MDMX, BAX, PUMA, and GADD45a expression. For apoptosis assays, cells were stained with Annexin V and analyzed by flow cytometry, with caspase-3/7 activation measured using fluorogenic substrates. For cell cycle analysis, propidium iodide staining and flow cytometry were performed. Clonogenic assays were conducted by plating cells in methylcellulose and scoring colonies after 7-14 days.
The cellular activity of sulanemadlin is evaluated in cancer cell lines with wild-type p53. Its effect on p53 stabilization and the expression of p53 target genes is measured. |
| Animal Protocol |
For xenograft efficacy studies, 5-10 × 10⁶ TP53 wild-type cancer cells were injected subcutaneously or intravenously into immunocompromised mice (e.g., NSG or nude mice). When tumors reached approximately 100-200 mm³, mice were randomized into treatment groups (n=5-10 per group) and received ALRN-6924 at doses ranging from 5-20 mg/kg via intravenous injection, typically administered once weekly or twice weekly for 2-4 weeks. Tumor volumes were measured twice weekly using calipers, and body weights were monitored for toxicity.
In animal studies, sulanemadlin is administered to mice bearing tumor xenografts. |
| ADME/Pharmacokinetics |
In the Phase I clinical trial, ALRN-6924 demonstrated dose-dependent pharmacokinetics when administered as an intravenous infusion. The compound and its primary active metabolite ALRN-8714 were measured in patient plasma using validated LC-MS/MS methods. Pharmacokinetic parameters including Cmax, AUC, and half-life were calculated by non-compartmental analysis. The pharmacodynamic response was measured by serum levels of macrophage inhibitory cytokine-1 (MIC-1), an established secreted biomarker of p53 activation, which showed dose-dependent increases following ALRN-6924 administration.
Pharmacokinetic properties of sulanemadlin are not detailed. |
| Toxicity/Toxicokinetics |
In the Phase I first-in-human trial (n=71), ALRN-6924 was generally well tolerated. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. At the 4.4 mg/kg dose level (arm A), dose-limiting toxicities included grade 3 hypotension, grade 3 alkaline phosphatase elevation, grade 3 anemia, and grade 4 neutropenia (one patient each). The maximum tolerated dose was established as 3.1 mg/kg on the once-weekly schedule (arm A), where only grade 3 fatigue was observed in one patient. No grade 3/4 thrombocytopenia was observed in any patient. Seven patients experienced infusion-related reactions, with three discontinuing treatment. No dose-limiting toxicities were observed in the twice-weekly schedule (arm B).
No toxicology data is provided. |
| References | |
| Additional Infomation |
Sulanemadlin (ALRN-6924) is a first-in-class dual MDM2/MDMX inhibitor that has advanced to Phase I/II clinical trials for TP53 wild-type cancers. The compound is a stapled α-helical peptide, where an all-hydrocarbon cross-link ("staple") locks the peptide in its biologically active α-helical conformation, conferring proteolytic stability and enhanced cell permeability. Unlike small-molecule MDM2-only inhibitors (e.g., nutlin, RG7388), ALRN-6924 targets both MDM2 and MDMX, which is important because MDMX overexpression is a common resistance mechanism to MDM2-selective agents. The compound has also been evaluated as a chemoprotective agent to protect healthy cells from chemotherapy-induced side effects in patients with TP53-mutant cancers. In preclinical studies, p53 activation by ALRN-6924 induces endogenous retrovirus expression and a viral mimicry response, potentially enhancing antitumor immunity and sensitivity to checkpoint therapy. The recommended Phase 2 dose is 3.1 mg/kg administered intravenously once weekly for 3 weeks every 28 days (schedule A).
Sulanemadlin is an orally potent peptide inhibitor that simultaneously inhibits mouse double microsome 2 (MDM2) and mouse double microsome X (MDMX), exhibiting potential antitumor activity. After oral administration, Sulanemadlin binds to MDM2 and MDMX, interfering with their interaction with the transcriptional activation domain of the tumor suppressor protein p53. By blocking the interactions between MDM2-p53 and MDMX-p53, p53 activity is restored, thereby inducing p53-mediated apoptosis in tumor cells. MDM2 and MDMX are negative regulators of p53 function and are often overexpressed in cancer cells. Sulanemadlin (CAS: 1451199-98-6) is a first-in-class stapled peptide that reactivates p53. |
| Molecular Formula |
C95H140N20O23
|
|---|---|
| Molecular Weight |
1930.25
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| Exact Mass |
1930.043
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| Elemental Analysis |
C, 59.11; H, 7.31; N, 14.51; O, 19.06
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| CAS # |
1451199-98-6
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| Related CAS # |
1451199-98-6; 1451199-80-6; 2000293-14-9
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| PubChem CID |
164182053
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| Sequence |
Ac-Leu-Thr-Phe-R8-Glu-Tyr-Trp-Ala-Gln-Leu-S5-Ala-Ala-Ala-Ala-Ala-{dAla}-NH2
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| SequenceShortening |
Ac-LTF-R8-EYWAQL-S5-AAAAA-{dAla}-NH2
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| Appearance |
White to off-white solid
|
| LogP |
3.6
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| Hydrogen Bond Donor Count |
23
|
| Hydrogen Bond Acceptor Count |
23
|
| Rotatable Bond Count |
37
|
| Heavy Atom Count |
138
|
| Complexity |
4220
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| Defined Atom Stereocenter Count |
18
|
| SMILES |
C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@](CCC/C=C/CCCCCC[C@@](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N1)CC2=CNC3=CC=CC=C32)CC4=CC=C(C=C4)O)CCC(=O)O)(C)NC(=O)[C@H](CC5=CC=CC=C5)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)C)(C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N)CC(C)C)CCC(=O)N
|
| InChi Key |
VDLGAZDAHPLOIR-XOZIGYNVSA-N
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| InChi Code |
InChI=1S/C95H140N20O23/c1-50(2)44-69(106-60(13)117)88(133)113-76(59(12)116)91(136)111-72(46-61-30-24-23-25-31-61)90(135)115-95(15)43-29-22-20-18-16-17-19-21-28-42-94(14,92(137)105-58(11)82(127)103-56(9)81(126)102-55(8)80(125)101-54(7)79(124)100-53(6)78(123)99-52(5)77(97)122)114-89(134)70(45-51(3)4)108-84(129)67(38-40-74(96)119)107-83(128)57(10)104-86(131)73(48-63-49-98-66-33-27-26-32-65(63)66)110-87(132)71(47-62-34-36-64(118)37-35-62)109-85(130)68(112-93(95)138)39-41-75(120)121/h17,19,23-27,30-37,49-59,67-73,76,98,116,118H,16,18,20-22,28-29,38-48H2,1-15H3,(H2,96,119)(H2,97,122)(H,99,123)(H,100,124)(H,101,125)(H,102,126)(H,103,127)(H,104,131)(H,105,137)(H,106,117)(H,107,128)(H,108,129)(H,109,130)(H,110,132)(H,111,136)(H,112,138)(H,113,133)(H,114,134)(H,115,135)(H,120,121)/t52-,53+,54+,55+,56+,57+,58+,59-,67+,68+,69+,70+,71+,72+,73+,76+,94+,95-/m1/s1
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| Chemical Name |
3-[(2S,5S,8S,11S,14S,17S,20S,32R)-32-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-20-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-amino-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]carbamoyl]-14-(3-amino-3-oxopropyl)-5-[(4-hydroxyphenyl)methyl]-8-(1H-indol-3-ylmethyl)-11,20,32-trimethyl-17-(2-methylpropyl)-3,6,9,12,15,18,33-heptaoxo-1,4,7,10,13,16,19-heptazacyclotritriacont-24-en-2-yl]propanoic acid
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| Synonyms |
Sulanemadlin; MP-4897; ALRN-6924
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ≥100 mg/mL (~51.8 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (1.30 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (1.30 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (1.30 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.5181 mL | 2.5903 mL | 5.1807 mL | |
| 5 mM | 0.1036 mL | 0.5181 mL | 1.0361 mL | |
| 10 mM | 0.0518 mL | 0.2590 mL | 0.5181 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03725436 | Active Recruiting |
Drug: MDM2/MDMX Inhibitor ALRN-6924 Drug: Paclitaxel |
HER2/Neu Negative TP53 wt Allele |
M.D. Anderson Cancer Center | January 24, 2019 | Phase 1 |
| NCT02909972 | Completed | Drug: ALRN-6924 Drug: ALRN-6924 in combination with cytarabine |
Acute Myeloid Leukemia Myelodysplastic Syndromes |
Aileron Therapeutics, Inc. | September 2016 | Phase 1 |
| NCT03654716 | Completed | Drug: ALRN-6924 Drug: Cytarabine |
Leukemia Brain Tumor Solid Tumor |
Dana-Farber Cancer Institute | November 1, 2018 | Phase 1 |
| NCT02264613 | Completed | Drug: ALRN-6924 | Solid Tumor Lymphoma Peripheral T-Cell Lymphoma |
Aileron Therapeutics, Inc. | October 2014 | Phase 1 Phase 2 |
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