These cell lines harbor wild-type p53, which, in response to treatment with doxorubicin or Nutlin-3, promoted the expression of well-known p53 target genes (CDKN1A, MDM2). Treatment with adenoviral vectors encoding canine p14ARF and interferon-β (IFNβ) resulted in cell death with liberation of immunogenic cell death markers in vitro and reduction of tumor progression when subcutaneous tumors in nude mice were treated with in situ gene therapy. These results indicate that adenovirus-mediated delivery of p14ARF and IFNβ is effective in a canine model of oral melanoma, supporting the feasibility of applying comparative oncology approaches to the development of this gene therapy strategy.

Molecular docking predicted a binding affinity of -7.1 kcal/mol, with baicalin occupying the p53-binding pocket of MDM2, whereas the known inhibitor Nutlin-3 showed a docking-predicted binding energy of -7.5 kcal/mol...In vitro assays showed that baicalin inhibited proliferation and induced morphological changes more prominently in MCF-7 cells compared to MDA-MB-231 cells, supporting a possible p53-dependent response. Overall, this study provides computational and preliminary cellular evidence that baicalin may interact with MDM2 and contribute to p53-mediated anticancer activity.

P1, N=24, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Jun 2027 | Trial primary completion date: Jun 2026 --> Jun 2027

P1, N=58, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Jun 2027 | Trial primary completion date: Jun 2026 --> Jun 2027

ALRN-6924 was well tolerated in children with on-target activity. Future efforts to evaluate this agent should focus on biomarker-selected populations, combination strategies, and evaluation of higher dose levels.

To identify functional mediators of carfilzomib (CFZ) resistance, we performed complementary gain-of-function CRISPR activation and pharmacological screening approaches...Pharmacologic inhibition of MDM2 with NVP-CGM097 synergized with CFZ across multiple PI-sensitive and PI-resistant MM cell lines, irrespective of TP53 status...Importantly, the combination retained efficacy in MM-stromal co-culture models and in primary patient samples, including cases harboring del(17p), while sparing normal peripheral blood mononuclear cells. Collectively, these findings identify MDM2 as a functional driver of PI resistance and support combined MDM2 and proteasome inhibition as a rational therapeutic strategy in MM, including TP53-deficient contexts.

This phase I trial (NCT03781986) assesses the safety and antitumor activity of an oral MDM2 inhibitor, alrizomadlin (APG-115), +/- carboplatin in TP53 wild type unresectable recurrent/metastatic salivary gland cancers (R/M SGC) with a planned 1:1 randomization to carboplatin chemotherapy. The RR was 15% with median progression free survival 10.5 months. These findings demonstrate encouraging tolerability of alrizomadlin monotherapy with antitumor activity in patients with TP53 wild type SGC, especially ACC.

P1, N=14, Completed, Novartis Pharmaceuticals | Terminated --> Completed

Notably, even topically applied ALRN-6924 afforded relative chemotherapy protection ex vivo. These results provide proof of principle for a strategy to selectively protect rapidly proliferating healthy epithelial tissues and their stem cells in patients with TP53-mutant cancers, which promises to protect against acute and permanent CIA.

[18F]1 showed favorable biodistribution characteristics in healthy mice, and preliminary PET/CT imaging studies revealed a higher uptake of [18F]1 in SJSA-1 xenografts compared to muscle at 1 h post-injection. Western blot analysis of SJSA-1 cells and immunohistochemical staining of SJSA-1 tumor sections confirmed high MDM2 expression and its localization in the nuclei of tumor cells, corroborating the PET imaging data.

The spirooxindoles 6b, 6k, and 6n attained the most pronounced activity in the MULTI-ARRAY MDM2-p53 complex assay with IC50 values of 1.26, 1.30, and 1.25 µM, respectively, in comparison with nutlin-3 (IC50 = 2.03 µM)...Molecular docking and molecular dynamics simulations justified the observed efficacy. Collectively, this study showcased a new class of potent p53-MDM2/MDMX dual inhibitors possessing a spirooxindole scaffold which can be subjected to future development.

Early-generation MDM2 inhibitors (e.g., RG7112, Idasanutlin) showed limited monotherapy efficacy and dose-limiting toxicities like thrombocytopenia, halting their development at early-phase clinical trials. In contrast, novel MDM2 inhibitors like APG-115 have advanced to Phase II trials, marking a significant breakthrough. Although not yet tested in dedicated osteosarcoma cohorts, their safety and efficacy in MDM2-amplified solid tumors provide a critical foundation for the development of precision medicine and combination regimens for osteosarcoma. Future efforts to accelerate drug development may leverage single-cell sequencing and AI-aided drug design to decipher osteosarcoma heterogeneity and optimize drug profiles for reduced toxicity.