Sulanemadlin (ALRN-6924)
Cancer Research Peptide
Sulanemadlin (ALRN-6924) is a potent, cell-permeable stapled peptide designed as a dual inhibitor of the MDM2 and MDMX proteins. It disrupts p53–MDM2 and p53–MDMX protein–protein interactions, leading to reactivation of p53 signaling in tumor cells retaining wild-type TP53. In ER-positive cancer cell lines with wild-type TP53 (e.g., MCF-7 and ZR-75-1), ALRN-6924 demonstrates dose-dependent anti-proliferative activity, with reported IC₅₀ values in the low nanomolar range. When combined with chemotherapeutic agents such as paclitaxel or eribulin, ALRN-6924 enhances antitumor efficacy. The combination induces p53 reactivation, cell cycle arrest, apoptosis in vitro, and tumor growth inhibition in vivo. ALRN-6924 is widely used as a reference stapled peptide for studying p53 pathway modulation and dual MDM2/MDMX inhibition.
Disease Target
Primary disease targets include solid tumors and hematological malignancies retaining wild-type TP53, particularly breast cancer, acute myeloid leukemia (AML), lymphomas, and other p53-dependent cancers driven by MDM2/MDMX overexpression.
Stapling Strategy
ALRN-6924 is synthesized using Fmoc-(S)-2-(4-pentenyl)alanine (Fmoc-(S5)-OH, CAS: 288617-73-2) and Fmoc-(R)-2-(7-octenyl)alanine (Fmoc-(R8)-OH, CAS: 945212-26-0), incorporated at i,i+4 positions during SPPS. A ruthenium-catalyzed ring-closing olefin metathesis generates the hydrocarbon staple, stabilizing the α-helical structure and enhancing cellular permeability and proteolytic stability.
Technical specification
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Sequency : | Ac-LTF(R8)EYWAQL(S5)AAAAAa-NH₂ |
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MW : | 1987.25 g/mol |
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Purity : | > 95% |
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Counter-Ion : | TFA Salts |
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Delivery format : | Lyophilized |
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CAS number : | 1451199-98-6 |
Price
| Product | Size | Price € |
Price $ |
| SB323-1mg | 1 mg | 602 | 722 |
| SB323-5mg | 5 mg | 763 | 916 |
| SB323-10mg | 10 mg | 1029 | 1235 |
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References
2021 Mar 4;23(1):29. doi: 10.1186/s13058-021-01406-x.
First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models
Abstract
Background
MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models.
Methods
Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel.
Results
ALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent.
Conclusion
The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.
2018 Nov 5:159:1-9. doi: 10.1016/j.ejmech.2018.09.044.
The development of piperidinones as potent MDM2-P53 protein-protein interaction inhibitors for cancer therapy
Abstract
In tumor cells, p53 is always inactivated due to the mutation or deletion of TP53 gene or inhibited by the overexpressed MDM2. Small-molecule induced restoring of p53 function by blocking MDM2-p53 protein-protein interactions has been highly pursued as an attractive therapeutic strategy for cancer therapy. To date, a large number of small-molecule inhibitors have been identified based on the compact and well-defined MDM2-p53 interactions, of which SAR405838, MK-8242, DS-3032b, NVP-CGM097, RG7112, HDM201, RG7388, ALRN-6924 and AMG 232 are undergoing clinical assessment at different phases for cancer therapy. This review is focused on the discovery and development of piperidinone-based MDM2-p53 inhibitors for cancer therapy, including the identification of hit compounds, hit-to-lead optimizations, binding models of ligands in the active site of MDM2, metabolic studies, and preclinical data of advanced piperidinone-based MDM2-p53 inhibitors. Additionally, acquired resistance of MDM2 inhibitors and potential toxicity toward normal tissues are briefly discussed.
2021 Oct 1;27(19):5236-5247. doi: 10.1158/1078-0432.CCR-21-0715.
Phase 1 Trial of ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Patients with Solid Tumors and Lymphomas Bearing Wild-type TP53
Abstract
Purpose: We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by mouse double minute 2 (MDM2) and MDMX to induce cell-cycle arrest or apoptosis in TP53-wild-type (WT) tumors.
Patients and methods: Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and antitumor effects in patients with solid tumors or lymphomas. In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B was twice-weekly for 2 weeks every 21 days.
Results:Seventy-one patients were enrolled: 41 in arm A (0.16-4.4 mg/kg) and 30 in arm B (0.32-2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLT) were grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the MTD in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; 3 discontinued treatment. In 41 efficacy-evaluable patients with TP53-WT disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, 2 had confirmed partial responses, and 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg.
Conclusions: ALRN-6924 was well tolerated and demonstrated antitumor activity.
