In mutant p53 cells, combination therapy may provide partial benefits. These findings support ALRN-6924 clinical development as targeted therapy for p53-functional CLL, particularly in combination strategies.

In addition, Nutlin-3 treatment decreased the EDmax value in p53 wild-type U2OS cells from 0.43 to 0.20. In summary, our method can identify p53-MDM2 interaction inhibitors in living cells, providing a quantitative in vivo supplement for traditional target-based drug discovery.

High doses of idasanutlin decreased the proliferation of T cells and depleted T cell numbers within the lymphocyte population, as we show in vitro and in vivo. These findings suggest that low doses of MDM2 antagonists may enhance immunotherapy, while higher doses could interfere with immunotherapy by p53-mediated cell cycle arrest and decreasing the proliferation of the immune cells.

Keap1-based degraders eliminate oncogenic KRAS and androgen receptor in cancer, antifolate-idasanutlin hybrids degrade Plasmodium falciparum DHFR-TS to overcome antifolate resistance, and PLK1 inhibition suppresses NLRP3 inflammasome activation to improve cardiac outcomes. Together, these innovations expand degrader and kinase-targeting strategies into oncology, infectious disease, and inflammatory cardiology.

The efficacy of the mouse double minute 2 homolog (MDM2) inhibitor (HDM201) and the Wee1 G2 checkpoint kinase (Wee1) inhibitor (adavosertib) was confirmed in both p53 wild-type (p53 WT) and p53 mutant (p53 MT) GIST cells. Our results highlight the importance of p53 status in guiding GIST treatment. p53 WT tumors respond to MDM2 inhibitors, while p53 MT tumors show greater sensitivity to Wee1 inhibitors, supporting p53 pathway targeting as a promising strategy for GIST patients.

Short hairpin RNA-mediated MDM2 knockdown and the p53-MDM2 inhibitors, nutlin-3 and RG7388, induced apoptosis in TP53_WT GC cells, indicating that activated MDM2 suppressed p53 protein levels and thereby attenuated the downstream p53 pathway activation, which was restored upon MDM2 knockdown or inhibitor treatment. Collectively, DNA-hypermethylated GC cases, HME_MLH1(-)/MSI and E-HME/EBV, follow a unique carcinogenic pathway to evade apoptosis in the absence of TP53 mutation, potentially making them responsive to therapeutic strategies that function primarily through the p53 pathway.

P1, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jul 2025 --> Jul 2027 | Trial primary completion date: Jul 2025 --> Jul 2027

P1, N=39, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Feb 2026 --> Sep 2025

Importantly, DNMT1 inhibition could provide a therapeutic alternative for neuroblastomas with p53 mutations, where p53 dependent mechanism is ineffective. Our results suggest that, if validated further, RG-7388, CM-272, and SGI-1027 could become effective therapeutic agents for treating aggressive neuroblastoma that may become resistant to first or second line of treatment.

Stabilization of p53 using the MDM2 inhibitor Nutlin-3 protected Tregs from losing their master transcription factor Foxp3 in vitro when cultured with the Th17 cytokines IL-6 and IL-1β, while p53 deficiency rendered Tregs more prone to Foxp3 loss...Additionally, these mice exhibited inflammation in the colon at homeostasis and increased severity of induced colitis. These results demonstrate a specific role for p53 in the maintenance of Treg stability in Th17-polarizing environments and present a possible target for improving Treg-based immunotherapies for diseases defined by intestinal inflammation, such as inflammatory bowel disease (IBD).

DRx-098D elicits its anti-cancer activity via a differentiated mechanism vs. idasanutlin (a phase 3 clinical candidate MDM2-p53 small-molecule inhibitor), inducing significantly superior growth inhibition against TP53 null HCT116 cells. Our preliminary data highlight, for the first time, the potential therapeutic utility of exploiting both MDM2 homo- and heterodimerization in TP53 wild-type and mutant cancers with an MDM2-derived disruptor peptide.

In 3D tumor spheroid models, IDLIN significantly inhibited tumor growth compared to control. This study presents IDLIN as a promising nanoformulation for delivery of IDA, demonstrating therapeutic potential in NSCLC treatment.