We demonstrate that MDM2 degraders KTX-049 and KT-253 overcome this limitation by collapsing the p53/MDM2 negative feedback loop. KTX-049 was >100-fold more potent than the MDM2 inhibitor DS-3032 across WT p53 MCC cell lines, and this superior potency was quantitatively supported by mechanistic mathematical modeling...Acquired resistance was strongly associated with acquisition of TP53 mutations, confirming on-target pathway pressure. These findings establish feedback architecture as a critical determinant of therapeutic response and position MDM2 degradation as a qualitatively distinct strategy that produces more durable pathway engagement than MDM2 inhibition, providing a preclinical rationale for prioritizing MDM2 degraders in WT TP53 MCC.

In cultured cell lines, exposure to MI-773, a MDM2 inhibitor, disturbed the expression of a significant number of genes and induced p21 protein expression in MDM2 inhibitor-sensitive cells. However, such changes were not observed in resistant cells. These results suggest that 3D-DST can predict biologically relevant drug sensitivity profiles in SMARCB1/INI1-deficient tumors.

Milademetan-mediated c-Myc depletion is accompanied by the induction of apoptosis and suppression of cell proliferation and prevents tumor growth, independently of p53 status. These findings reveal an unexpected mechanism by which MDM2 coordinates two of the most frequently altered pathways in cancer and provide a rationale for targeting c-Myc-driven tumors, including those lacking functional p53, through MDM2 modulators.

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.