Nutlin-3

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.

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).

Finally, we found that cells expressing the p.E339_F341del variant were insensitive to inhibition of MDM2 by nutlin-3 confirming the functional defect. We conclude that the in-frame germline c.1015_1023del TP53 variant encodes a transcriptionally inactive protein and promotes LFS with a high penetrant cancer phenotype.

We also identified two drugs, AMG232 and Nutlin-3, that exhibited treatment effects similar to P. chinensis in A549 cells. Western blot analysis confirmed the alteration of the relevant proteins, aligning with our computational predictions. Furthermore, 23-hydroxybetulinic acid, a key active compound of P. chinensis, demonstrated the ability to inhibit the p53-MDM2 interaction by binding to the same pocket on the MDM2 protein.

p53, often mutated in cancer, is reactivated using MDM2 antagonist Nutlin-3, refunctionalizing compound APR-246, or stapled peptides. HIF-1α, which regulates hypoxic responses and angiogenesis, is inhibited by agents like acriflavine or stabilized in anemia therapies by HIF-PHD inhibitor roxadustat...AP-1, implicated in cancer and arthritis, can be inhibited by T-5224 or kinase inhibitors JNK and p38 MAPK...Challenges remain, including the structural inaccessibility of TFs, functional redundancy, off-target effects, and delivery barriers. Despite these challenges, transcription factor modulation is emerging as a viable and promising therapeutic approach, with ongoing research focusing on specificity, safety, and efficient delivery methods to realize its full clinical potential.

p53 overexpression/knockdown, siRNA-mediated ferredoxin reductase (FDXR)/FDX1 knockdown, and the p53 activators CP-31398 and nutlin-3 were employed to elucidate the associated molecular mechanisms. These findings revealed that p53 enhances elesclomol-Cu-induced cuproptosis in HCC via FDXR-mediated FDX1 upregulation. This study provides mechanistic insights into p53's role in cuproptosis and may serve as a basis for targeting copper metabolism in therapeutic strategies for HCC.

Here we report the discovery of novel MDM2-recruiting PROTACs incorporating rac-Nutlin-3 as a ligand with an easier synthetic tractability, further demonstrating its potential in this technology. The most promising degrader, PROTAC 3, showed preferential degradation of the BRD4 short isoform and c-Myc compared with MZ1, a validated VHL-based PROTAC.

Nutlin-3 combined with erastin or RSL3 reduced absolute p-4EBP-1 levels in NDDLS-1 cells and p-p70S6 levels in both cell lines, with no significant impact on the p-4EBP-1/4EBP-1 and p-p70S6/p70S6 ratios. These results indicate that ferroptosis is a therapeutic vulnerability in the response to MDM2 inhibition in DDLPS. Furthermore, combining MDM2 inhibitors with ferroptosis-inducing agents may provide a potential therapeutic strategy for DDLPS and the role of mTOR in the pro-apoptotic effect of these combinations deserve further investigation.

Then the PROTAC was conjugated with JZL184 analog and the MDM2 inhibitor Nutlin-3 analog. Experimental results validated that the designed JN-PROTAC effectively induced MAGL targeted degradation and concomitantly enhanced P53 activation via MDM2 inhibition and is capable of inhibiting the progression of patient-derived GSCs in vivo. This work presents a proof-of-concept PROTAC design tailored for GSCs, potentially addressing the occurrence challenges for GBM.

Moreover, the p53 activator Nutlin-3 A accelerated Nanog degradation, while the p53 inhibitor Pifithrin-α stabilized Nanog...Inhibition of p38 and AKT with SB203580 and LY294002 reduced Nanog expression and partially restored Type II collagen levels...The injected zebrafish exhibited structural defects in craniofacial cartilage, confirming Nanog's involvement in chondrocyte differentiation. These findings suggest that Nanog induces chondrocyte dedifferentiation, and this process can be modulated via the p53/KLF4 and p38/AKT pathways.

Our results highlight the translational value of the head and neck organoid models not only for patient stratification but also for mechanistic validation of therapy responsiveness of specific cancer drivers.

Additionally, the administration of LY294003 and nutlin-3 effectively inhibits proliferation and migration, while promoting apoptosis in HCT116 cells (P<0.001)...Also, shHM13 decreased the level of p-PI3K/PI3K and p-AKT/AKT, upregulated p53 and p21 activities. It can thus be concluded that HM13 might be a novel oncogene in CRC and regulates proliferation, migration and apoptosis by modulating the PI3K/Akt and p53 signaling pathways.