ArticlePediatric blood & cancer2016
Initial Testing (Stage 1) of MK-8242-A Novel MDM2 Inhibitor-by the Pediatric Preclinical Testing Program.
Article in Pediatric blood & cancer, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 35 citations in OpenAlex.
- Targeting p53 pathways: mechanisms, structures, and advances in therapy.Signal transduction and targeted therapy · 2023Pooled it
- Research Progress on Small Molecule Inhibitors of MDM2-p53 Protein-protein Interaction.Anti-cancer agents in medicinal chemistry · 2026Review
- Development of MDM2-Targeting PROTAC for Advancing Bone Regeneration.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Harnessing p53 for targeted cancer therapy: new advances and future directions.Transcription · 2025Review
- Lessons learned from 20 years of preclinical testing in pediatric cancers.Pharmacology & therapeutics · 2024Review
- Discovery of MD-265: A Potent MDM2 Degrader That Achieves Complete Tumor Regression and Improves Long-Term Survival of Mice with Leukemia.Journal of medicinal chemistry · 2024Article
- Insights into the Interaction Mechanisms of Peptide and Non-Peptide Inhibitors with MDM2 Using Gaussian-Accelerated Molecular Dynamics Simulations and Deep Learning.Molecules (Basel, Switzerland) · 2024Article
- Recent advances in targeting the "undruggable" proteins: from drug discovery to clinical trials.Signal transduction and targeted therapy · 2023Review
- Review
- Therapeutic Strategies to Activate p53.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Potential of rescue and reactivation of tumor suppressor p53 for cancer therapy.Biophysical reviews · 2022Review
- PROTAC Degraders with Ligands Recruiting MDM2 E3 Ubiquitin Ligase: An Updated Perspective.Acta materia medica · 2022Article
- Molecular targeting therapies for neuroblastoma: Progress and challenges.Medicinal research reviews · 2021Review
- Targeting the p53-MDM2 pathway for neuroblastoma therapy: Rays of hope.Cancer letters · 2021Review
- MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy.Frontiers in oncology · 2021Review
- Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives.Acta pharmaceutica Sinica. B · 2020Review
- Article
- Systematic target actionability reviews of preclinical proof-of-concept papers to match targeted drugs to paediatric cancers.European journal of cancer (Oxford, England : 1990) · 2020Review
- Targeting MDM2 for novel molecular therapy: Beyond oncology.Medicinal research reviews · 2020Review
- Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer.Frontiers in pharmacology · 2020Review
Corrections and comments
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Authors and funding
13 authors at 10 institutions in 2 countries.
Funding
Abstract
backgroundMK-8242 is an inhibitor of MDM2 that stabilizes the tumor suppressor TP53 and induces growth arrest or apoptosis downstream of TP53 induction. PROCEDURES: MK-8242 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10.0 μM and against the PPTP in vivo xenograft panels using oral gavage on Days 1-5 and Day 15-19 at a dose of 125 mg/kg (solid tumors) or 75 mg/kg (acute lymphoblastic leukemia [ALL] models).
resultsThe median IC50 for MK-8242 was 0.07 μM for TP53 wild-type cell lines versus >10 μM for TP53 mutant cell lines. MK-8242 induced a twofold or greater delay in time to event in 10 of 17 (59%) of TP53 wild-type solid tumor xenografts, excluding osteosarcoma xenografts that have very low TP53 expression. Objective responses were observed in seven solid tumor xenografts representing multiple histotypes. For the systemic-disease ALL panel, among eight xenografts there were two complete responses (CRs) and six partial responses (PRs). Two additional MLL-rearranged xenografts (MV4;11 and RS4;11) grown subcutaneously showed maintained CR and PR, respectively. The expected pharmacodynamic responses to TP53 activation were observed in TP53 wild-type models treated with MK-8242. Pharmacokinetic analysis showed that MK-8242 drug exposure in SCID mice appears to exceed that was observed in adult phase 1 trials.
conclusionsMK-8242-induced tumor regressions across multiple solid tumor histotypes and induced CRs or PRs for most ALL xenografts. This activity was observed at MK-8242 drug exposures that appear to exceed those observed in human phase 1 trials.
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Registered trials
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