idasanutlin (RG7388)

To investigate whether MDM2 can serve as tumor-specific PROTAC E3 in certain setting, we analyzed the benchmark compound A1874 (JQ1-Idasanutlin chimera targeting BRD4) under various conditions that affect MDM2 expression and activity. Importantly, A1874 showed on average ~12-fold higher potency in tumor cells with MDM2 amplification compared to non-amplified cells, correlating with enhanced cytotoxicity. The results suggest that tumors with MDM2 amplification or overexpression can be selectively targeted using PROTAC approach.

These results support further evaluation of combination therapies with corresponding small-molecule inhibitors (currently pursued for therapy of other cancers) toward clinical testing as novel strategies to increase the efficacy of CLM-based ADCs such as GO and InO.

The pomalidomide/thalidomide-based series (BP1-BP5) exhibited strong antiproliferative activity against leukemia and multiple myeloma cells, accompanied by degradation of CRBN neosubstrates. The hit compounds from both series, BP1 (DC50, 24 h = 20 nM, Dmax, 24 h = 99%) and BP6 (DC50, 24 h = 81 nM, Dmax, 24 h = 93%), demonstrated highly efficient and selective HDAC8 degradation. Pretreatment with BP6 enhanced the tumor suppressor p53 stability, thereby significantly increasing the sensitivity of leukemia cells to the MDM2 antagonist idasanutlin than PCI-34051, highlighting its unique potential for combinatorial therapy without impacting neosubstrates.

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.

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.

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.

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.

There were several grade 3-4 toxicities, particularly cytopenias in arm IDA. While this study was limited by small sample sizes, there were observations of clinical activity, including one exceptional responder, that warrant further investigation.

This was further supported by the use of ROS scavengers, N-acetylcysteine (NAC), and Ferrostatin-1 (Fer-1), which attenuated these effects. Furthermore, immunohistochemical (IHC) analysis of an NSCLC tissue microarray confirmed a strong positive correlation between p-p38 and NOXA expression. Clinical data analysis further suggested that the p-p38/NOXA axis might be a potential prognostic biomarker for overall survival (OS) in NSCLC patients.

We found that the clinically relevant p53 activator Idasanutlin suppresses the HSF1-HSR activity in HSP90 inhibitor-based therapies...Likewise, p53-mutated PDOs respond to dual HSF1-HSP90 inhibition, providing a strategy to target CRC independent of the p53 status. In sum, we provide new options to improve HSP90-based therapies to enhance CRC therapies.