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A specimen of the Other drawer Drawer G · Other

Sulanemadlin

Investigational

First-in-class stapled alpha-helical peptide and dual MDM2/MDMX inhibitor that reactivates wild-type p53 tumor suppressor function. Phase 1/2 trials demonstrated 59% disease control rate with notably low hematologic toxicity compared to MDM2-only inhibitors. Novel chemoprotection application being developed for retinoblastoma with Advancium Biosciences partnership.

ALRN-6924 · MP-4897

Research evidence
Moderate

18 human studies

Preclinical
36%
Human research
64%

Based on 28 cited sources

Numeric assessment unreviewed

A historical numeric score is recorded but has not passed a current, compound-specific assessment review. No numeric score is displayed.

This is a limitation of the numeric assessment, not a measured absence of benefit. It does not re-review the separately recorded catalogue classification or establish efficacy or safety.

Scoring context and limitations
~
Evidence Level
moderate
Phase 2 clinical trials for solid tumors.
Investigational
Identity
SCALE · 1:1 N-TERMINUS C-TERMINUS 15 AA · ~2,100 Da
Also Known As
ALRN-6924 • MP-4897
Class
Stapled alpha-helical peptide
Length
15 amino acids
Mol. weight
~2,100 Da
Sequence
Hydrocarbon-stapled i,i+7 helix mimicking p53 TAD
Molecular Structure
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hydrophobic
Polar
Positive
Negative

Sulanemadlin reactivates the p53 tumor suppressor pathway by blocking its negative regulators MDM2 and MDMX.

How It Works (Simplified)

Sulanemadlin acts as a “decoy” that frees p53 to resume its cancer-fighting function:

p53 Liberation

Binds to MDM2 and MDMX proteins that normally suppress p53, freeing p53 to activate tumor suppressor genes.

Dual Targeting

Unlike small molecule MDM2 inhibitors, blocks BOTH MDM2 and MDMX simultaneously, preventing resistance escape.

Cancer Cell Death

Activated p53 triggers apoptosis in cancer cells through PUMA, BAX, and NOXA gene expression.

Chemoprotection

In normal cells, p53 activation causes temporary G1 arrest, allowing them to “hide” during chemotherapy exposure.

Key Research: Saleh MN et al. (USA, 2021) demonstrated a 59% disease control rate with low hematologic toxicity in a first-in-human Phase 1 trial. PMID:34301750

Important Limitations

  • Requires TP53 wild-type status; ineffective in TP53-mutant tumors
  • Currently investigational with no regulatory approvals
  • Administered IV only; oral formulation not available
  • Long-term safety data limited to Phase 1/2 trial durations
i. MDM2/MDMX-p53 Pathway · Tumor Suppression
SulanemadlinBinds MDM2 + MDMXp53 released from suppressionp53 activates target genes (p21, PUMA, BAX)Cell cycle arrest + Apoptosis in cancer cells
ii. Chemoprotection Pathway · Normal Cell Protection
Sulanemadlin (pre-chemo)p53 activation in normal cellsTransient G1 arrestNormal cells protected during chemoEffect reverses after clearance
Mechanism Dual MDM2/MDMX binding displacing p53, reactivating tumor suppressor function
Established 12 direct studies
Benefit shown to induce cancer cell death in TP53 wild-type tumors
Evidence Level
Moderate
4 Human
6 Animal
8 In Vitro
Mechanism Transient p53-mediated G1 arrest in normal cells protecting from chemotherapy
Supported 5 direct studies
Benefit suggested to protect normal tissues from chemotherapy-induced toxicity
Evidence Level
Low
1 Human
3 Animal
4 In Vitro
Mechanism High-affinity MDMX inhibition overcoming resistance seen with MDM2-only inhibitors
Supported 6 direct studies
Benefit appears to maintain efficacy in MDMX-overexpressing tumors
Evidence Level
Low
1 Human
4 Animal
5 In Vitro
Mechanism Confidence
Established
Supported
Emerging
Evidence Level
High
Moderate
Low
Very Low
Phase 01 1
Week 1-2

Administered by intravenous infusion on a weekly or twice-weekly schedule. Rapid p53 pathway activation confirmed by serum MIC-1 elevation, a pharmacodynamic biomarker. Dose-dependent pharmacokinetic and pharmacodynamic response observed.

PMID:34301750
Phase 02 2
Week 2-4

Disease stabilization may become apparent. Tumor marker changes and imaging assessment typically at cycle 2. In the separately investigated chemoprotection setting, low doses transiently arrest the cell cycle in healthy tissues; clinical benefit was not confirmed in a randomized study.

PMID:37439511
Phase 03 3
Week 4-8

Response assessment per RECIST criteria. Confirmed complete and partial responses were observed across schedules. Continued tolerability with low rates of dose-limiting toxicity. Cumulative fatigue possible.

PMID:34301750
Phase 04 4
Week 8+

Durable disease control in responding patients, with six patients treated for over one year. Notably, no grade 3/4 thrombocytopenia was observed, reflecting a favorable hematologic safety profile.

PMID:34301750

Research-based observations

This timeline reflects observations from published clinical and preclinical studies. Individual responses may vary significantly. This is not a guarantee of effects or a dosing schedule. Consult qualified healthcare providers for personalized guidance.

Synergistic
Compatible
Caution
Avoid

Idasanutlin

Caution
Caution

Both target MDM2-p53 pathway. Combining MDM2 inhibitors could cause excessive p53 activation and increased toxicity. Not recommended for co-administration.

Navtemadlin

Caution
Caution

Overlapping MDM2 inhibition mechanism. Concurrent use may increase risk of hematologic toxicity. Clinical combination not studied.

Milademetan

Caution
Caution

Similar MDM2-targeting mechanism. Potential for additive toxicity if combined. No clinical data on co-administration.

Research Note: Interaction data is based on published literature, mechanistic understanding, and theoretical considerations. Most peptide combinations lack direct clinical study. This information is for educational purposes only and does not constitute medical advice. Always consult qualified healthcare providers.

28 Sources 18 Human 10 Preclinical

Key Studies Cited

RCT Saleh MN et al. 2021
PMID:34301750
Animal Chang YS et al. 2013
PMID:23946421
Animal Guerlavais V et al. 2023
PMID:37439511
Review Falandry C et al. 2023
PMID:37036091
Animal Bernal F et al. 2010
PMID:21075307

Use the source links in the research discussion above to inspect the referenced records.

This dossier synthesizes available evidence from peer-reviewed literature, regulatory documents, and clinical trial registries. Evidence strength labels summarize the cited material for this entry and should be read alongside its population, model, and study limitations.

For complete methodology details, see our Methodology page.

Important Disclaimer

This dossier is for educational purposes only and does not constitute medical advice. Always consult a qualified healthcare provider before making health decisions.

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Conditions Studied

3 entries