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.

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.

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.

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

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.

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.

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

This reduces p53 degradation and consequently activates p53, leading to p21 transcription and the induction of cellular senescence. Treatment with doxorubicin (Dox) or nutlin-3a further enhances p53-mediated transcriptional activation of p21, and their combination with LTβR depletion exerts an additive effect in promoting cellular senescence.

Further, DPMI-ω inhibited B16 melanoma growth in vivo and, when combined with an anti-PD1 antibody, powerfully augmented the efficacy of immunotherapy by expanding CD3+/CD8+ cytotoxic T cells and suppressing CD4+/CD25+ regulatory T cells. Our work validates the design of a therapeutically viable anticancer peptide, showcasing its potential in combination therapy to treat patients with tumors that are otherwise resistant or poorly responsive to antitumor immunotherapy.

We demonstrated that a mtp53-MDM2/MDMX complex promoted 53BP1-MDC1 interactions by showing that mtp53-MDM2/MDMX complex disruptors, Nutlin 3a and ALRN-6924, reduced the 53BP1-MDC1 nuclear interactions (especially in S-phase)...We found that MDM2-deficient cells have increased poly-ADP-ribosylation on chromatin which supports the possibility that a mtp53-MDM2/MDMX pathway promotes aberrant DNA repair. Taken together, our data suggest that a mtp53-MDM2/MDMX complex orchestrates DNA repair machinery activity on chromatin, thus priming cancer cells for persistent DNA damage repair (CPR).

Moreover, we found that MDMX Ser-314 phosphorylation, a consensus sequence of CDK4/6, increases MDMX stability, which subsequently affects MDM2 and p53 degradation and could be reversed by the CDK4/6 inhibitor Palbociclib...Consequently, p53 inactivation promotes their survival, proliferation, and resistance to chemotherapy-induced apoptosis. The figure was created in BioRender.com.

This study reveals that Mdmx can control cell invasion through RhoA stabilisation/activation, which is potentially linked to the reported anti-oncogenic functions of Mdmx. As inhibitors of the NEDD8 pathway are in clinical trials, the status of Mdmx may be a critical determinant for the anti-tumour effects of these inhibitors.