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.

We previously identified MDM2 as a therapeutic vulnerability in RTs and showed that treatment with the MDM2 inhibitor idasanutlin (IDA) increased survival in mice bearing MRT xenografts...We hypothesized that combining IDA with selinexor (SEL), a CNS penetrant XPO1 inhibitor, would potentiate p53-mediated activation and increase therapeutic response in vivo...The BCL-2 family of proteins was identified as key modulators of intrinsic and acquired resistance. Combining MDM2 inhibitors and XPO1 inhibitors is a promising therapeutic strategy for treating children with ATRT.

In p53-wild-type, PPM1D-mutant DIPG neurospheres (BT869), ATSP-7041 exhibited ∼125-fold greater antitumor activity than the HDM2-selective antagonist RG7388, consistent with elevated HDMX expression. This feasibility study provides proof of concept for on-target p53 reactivation in DIPG using a BBB-penetrant dual HDM2/HDMX inhibitor delivered by the MIND platform. The findings support a translational path for ALRN-6924, the clinical analogue of ATSP-7041, in DIPG and potentially other brain tumors that retain wild-type p53 but remain incurable because of drug resistance and restricted CNS access.

P2, N=0, Withdrawn, National Cancer Institute (NCI) | N=15 --> 0 | Trial completion date: Dec 2027 --> Mar 2026 | Not yet recruiting --> Withdrawn | Trial primary completion date: Dec 2027 --> Mar 2026

P1, N=28, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Jul 2027 --> Mar 2026 | Trial primary completion date: Jul 2027 --> Mar 2026

Study objectives are to isolate the contribution of add-on navtemadlin by assessing SVR and TSS 24-weeks after randomization from the pre-randomization baseline and to demonstrate that this contribution is clinically meaningful using established SVR and TSS endpoints from the pre-ruxolitinib treatment baseline. Secondary endpoints include progression-free survival, leukemia-free survival, and OS.Clinical Trial Registration: NCT06479135 (ClinicalTrials.gov); EUCT 2023-504724-25-00 (EUClinicalTrials.EU).

P1/2, N=47, Active, not recruiting, Centre Leon Berard | Recruiting --> Active, not recruiting | Trial completion date: Jul 2026 --> Feb 2027 | Trial primary completion date: Jan 2026 --> Feb 2027

APG-115 effectively inhibits proliferation, induces apoptosis, and enhances radiosensitivity in p53 wild-type colorectal cancer. These findings support APG-115 as a promising therapeutic candidate for colorectal cancers retaining functional p53.

In p53-wild-type, PPM1D-mutant DIPG neurospheres (BT869), ATSP-7041 exhibited ~125-fold greater anti-tumor activity than the HDM2-selective antagonist RG7388, consistent with elevated HDMX expression. This feasibility study provides proof-of-concept for on-target p53 reactivation in DIPG using a BBB-penetrant dual HDM2/HDMX inhibitor delivered by the MIND platform. The findings support a translational path for ALRN-6924, the clinical analog of ATSP-7041, in DIPG and potentially other brain tumors that retain wild-type p53 but remain incurable due to drug resistance and restricted CNS access.

P1/2, N=41, Active, not recruiting, University of Michigan Rogel Cancer Center | Trial completion date: Jun 2026 --> Nov 2026 | Trial primary completion date: Dec 2025 --> May 2026